Modulators of acetylcholine receptors

ABSTRACT

The present invention provides a class of pyridine compounds which are modulators of acetylcholine receptors, i.e., compounds which displace acetylcholine receptor ligands from their binding sites. Invention compounds may act as agonists, partial agonists, antagonists or allosteric modulators of acetylcholine receptors, and are useful for a variety of therapeutic applications, such as the treatment of Alzheimer&#39;s disease and other disorders involving memory loss and/or dementia; disorders of attention and focus; disorders of extrapyramidal motor function; mood and emotional disorders; substance abuse including withdrawal syndromes and substitution therapy; neuroendocrine disorders and dysregulation of food intake, including bulimia and anorexia; disorders of nociception and control of pain; autonomic disorders including dysfunction of gastrointestinal motility and function; pheochromocytoma; cardiovascular dysfunction including hypertension and cardia arrhythmias, comedication in surgical procedures, and the like.

RELATED APPLICATIONS

This application is a continuation-in-part of U.S. Ser. No. 08/337,640,filed Nov. 10, 1994, U.S. Pat. No. 5,594,017, the entire contents ofwhich are hereby incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to novel compounds which are capable ofmodulating acetylcholine receptors. Invention compounds are useful, forexample, for treatment of dysfunction of the central or autonomicnervous systems including dementia, cognitive disorders,neurodegenerative disorders, extrapyramidal disorders, convulsivedisorders, cardiovascular disorders, endocrine disorders, pain,gastrointestinal disorders, eating disorders, affective disorders, anddrug abuse. In addition, the present invention relates to pharmaceuticalcompositions containing these compounds, as well as various usestherefor.

BACKGROUND OF THE INVENTION

By modulation of neurotransmitter release (including dopamine,norepinephrine, acetylcholine and serotonin) from different brainregions, acetylcholine receptors are involved in the modulation ofneuroendocrine function, respiration, mood, motor control and function,focus and attention, concentration, memory and cognition, and themechanisms of substance abuse. Ligands for acetylcholine receptors havebeen demonstrated to have effects on attention, cognition, appetite,substance abuse, memory, extrapyramidal function, cardiovascularfunction, pain and gastrointestinal motility and function. Thedistribution of acetylcholine receptors that bind nicotine, i.e.,nicotinic acetylcholine receptors, is widespread in the brain, includingthe basal ganglia, limbic system, cerebral cortex and mid- andhind-brain nuclei. In the periphery, the distribution includes muscle,autonomic ganglia, the gastrointestinal tract and the cardiovascularsystem.

Acetylcholine receptors have been shown to be decreased, inter alia, inthe brains of patients suffering from Alzheimer's disease or Parkinson'sdisease, diseases associated with dementia, motor dysfunction andcognitive impairment. Such correlations between acetylcholine receptorsand nervous system disorders suggest that compounds that modulateacetylcholine receptors will have beneficial therapeutic effects formany human nervous system disorders. Thus, there is a continuing needfor compounds which can selectively modulate the activity ofacetylcholine receptors. In response to such need, the present inventionprovides a new family of compounds which modulate acetylcholinereceptors.

BRIEF DESCRIPTION OF THE INVENTION

In accordance with the present invention, we have discovered that theclass of pyridine compounds defined herein are modulators ofacetylcholine receptors.

The compounds of the present invention are capable of displacing one ormore acetylcholine receptor ligands, e.g., ³ H-nicotine, from mammaliancerebral membrane binding sites. Invention compounds may act asagonists, partial agonists, antagonists or allosteric modulators ofacetylcholine receptors. Therapeutic indications for compounds withactivity at acetylcholine receptors include diseases of the centralnervous system such as Alzheimer's disease and other disorders involvingmemory loss and/or dementia (including AIDS dementia); cognitivedysfunction (including disorders of attention, focus and concentration),disorders of extrapyramidal motor function such as Parkinson's disease,progressive supramuscular palsy, Huntington's disease, Gilles de laTourette syndrome and tardive dyskinesia; mood and emotional disorderssuch as depression, panic, anxiety and psychosis; substance abuseincluding withdrawal syndromes and substitution therapy; neuroendocrinedisorders and dysregulation of food intake, including bulemia andanorexia; disorders of nociception and control of pain; autonomicdisorders including dysfunction of gastrointestinal motility andfunction such as inflammatory bowel disease, irritable bowel syndrome,diarrhea, constipation, gastric acid secretion and ulcers;pheochromocytoma; cardiovascular dysfunction including hypertension andcardia arrhythmias, as well as co-medication uses in surgicalapplications.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there are provided compoundshaving the structure (Formula I): ##STR1## wherein: A is a 1, 2 or 3atom bridging species which forms part of a saturated or monounsaturated5-, 6- or 7-membered ring including N⁷, C⁸, C⁹ and B;

B is selected from --O--, --S--, --NR¹⁰ --, wherein R¹⁰ is selected fromhydrogen, lower alkyl, aryl, substituted aryl, alkylaryl, substitutedalkylaryl, arylalkyl, substituted arylalkyl; --C¹⁰ HR^(10a) --, whereinR^(10a) is selected from hydrogen, lower alkyl, hydroxyalkyl, aryl,aryloxyalkyl, fluoro, trifluoromethyl, cyano, cyanomethyl, --OR',--NR'₂, or --SR', wherein each R' is independently hydrogen, loweralkyl, alkenyl, alkynyl or aryl, provided, however, that neither the--NR'₂ nor the --SR' functionality is conjugated with an alkenyl oralkynyl functionality; or B is ═C¹⁰ R^(10a) -- or ═N--, provided thereis no double bond in the ring between A and B, or between B and C⁹ whenthere is a double bond between N⁷ and C⁸, and provided that B is not aheteroatom when A is a 1 atom bridging species;

R², R⁴, R⁵ and R⁶ are each independently selected from hydrogen, alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, alkylaryl, substituted alkylaryl, arylalkyl, substitutedarylalkyl, heterocyclic, substituted heterocyclic, trifluoromethyl,halogen, cyano, nitro;

--S(O)R', --S(O)₂ R' or --S(O)₂ NHR', wherein each R' is as definedabove, provided, however, that when R², R⁴, R⁵ or R⁶ is however,--S(O)R', R' is not hydrogen, alkenyl or alkynyl, and provided that whenR², R⁴, R⁵ or R⁶ is --S(O)₂ NHR', R' is not alkenyl or alkynyl;

--C(O)R", wherein R" is selected from hydrogen, alkyl, substitutedalkyl, alkoxy, alkylamino, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, aryloxy, arylamino,alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl,heterocyclic, substituted heterocyclic or trifluoromethyl, provided,however, that the carbonyl functionality is not conjugated with analkenyl or alkynyl functionality;

--OR'", wherein R'" is selected from hydrogen, alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl,substituted alkylaryl, arylalkyl, substituted arylalkyl, aroyl,substituted aroyl, heterocyclic, substituted heterocyclic, acyl,trifluoromethyl, alkylsulfonyl or arylsulfonyl, provided, however, thatthe --OR'" functionality is not conjugated with an alkenyl or alkynylfunctionality;

--NR'"₂, wherein each R'" is independently as defined above, or each R'"and the N to which they are attached can cooperate to form a 4-, 5-, 6-or 7-membered ring; provided, however, that the --NR'"₂ functionality isnot conjugated with an alkenyl or alkynyl functionality;

--SR"", wherein R"" is selected from hydrogen, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl,substituted arylalkyl, heterocyclic, substituted heterocyclic ortrifluoromethyl, provided, however, that the --SR"" functionality is notconjugated with an alkenyl or alkynyl functionality; or

--SiR'""₃, wherein R'"" is selected from alkyl or aryl;

R⁷ is selected from hydrogen, lower alkyl, aryl, substituted aryl,alkylaryl, or substituted alkylaryl, or R⁷ is absent when there is adouble bond between N⁷ and C⁸ ; and

R⁹ and R^(9a) are each independently selected from hydrogen, loweralkyl, hydroxyalkyl, aryl, aryloxyalkyl, fluoro, trifluoromethyl, cyano,cyanomethyl, --OR', --NR'₂, or --SR', wherein each R' is as definedabove, provided, however, that neither the --NR'₂ nor the --SR'functionality is conjugated with an alkenyl or alkynyl functionality.

Specifically excluded from the above definition of compounds embraced byFormula I are nicotine (i. e., wherein A=--CH₂ --, B=--CH₂ --, R², R⁴,R⁵, R⁶, R⁹ and R^(9a) =H and R⁷ =methyl); nornicotine (i.e., whereinA=--CH₂ --, B=--CH₂ --, and R², R⁴, R⁵, R⁶, R⁷, R⁹ and R^(9a) are eachH; anabasine and N-methyl anabasine (i. e., wherein A=--CH₂ CH₂ --,B=--CH₂ --, R², R⁴, R⁵, R⁶, R⁹ and R^(9a) =H, and R⁷ =H or methyl,respectively); anabaseine (i.e. , wherein A=--CH₂ CH₂ --, B=--CH₂ --,R², R⁴, R⁵, R⁶, R⁹ and R^(9a) are hydrogen and R⁷ is absent, due to thepresence of a double bond between N⁷ and C⁸); anatabine (i.e., whereinA=--CH₂ CH═, B=--CH═, and each of R², R⁴, R⁵, R⁶, R⁷, R⁹ and R^(9a) arehydrogen); N-methyl-2-oxoanabasine (i. e. , wherein A=--C(O)CH₂ --,B=--CH₂ --, R², R⁴, R⁵, R⁶, R⁹ and R^(9a) are hydrogen and R⁷ =methyl);myosmine (i. e., wherein A=--CH₂ --, B=--CH₂ --, R², R⁴, R⁵, R⁶, R⁹ andR^(9a) are hydrogen, and R⁷ is absent, due to the presence of a doublebond between N⁷ and C⁸); cotinine (i.e., wherein A=--C(O)--, B=--CH₂ --,R², R⁴, R⁵, R⁶, R⁹ and R^(9a) =H, and R⁷ =methyl); as well as thecompounds wherein A=--CH₂ --, B=--CH₂ --, R² =H or Br, R⁴, R⁶, R⁹ andR^(9a) =H, R⁵ =H or methyl, and R⁷ =methyl; compounds wherein A=--CH₂--, B=--CH₂ --, R², R⁴, R⁵ and R⁶ =H or alkyl, R⁷ is alkyl and R⁹ andR^(9a) =hydrogen; compounds wherein A=--CH₂ --, --C(O)-- or --CH(CH₂F)--, B=--CHR^(10a) -- (wherein R^(10a) is H, lower alkyl, hydroxyalkyl,F, cyano, cyanomethyl or --OR', wherein R'=hydrogen or methyl), R², R⁴,R⁵ and R⁶ =H, R⁷ is methyl and R⁹ and R^(9a) =hydrogen, methyl,fluorine, cyanomethyl, cyano or hydroxyalkyl; compounds wherein A=--CH₂--, --CH₂ CH₂ -- or --CH₂ CH═, B=--CH₂ -- or --CH═, R² and R⁶ =loweralkyl or arylalkyl, R⁴, R⁵, R⁹ and R^(9a) =H and R⁷ =hydrogen or methyl;compounds wherein A=--CH₂ --, B=--CH₂ --, R², R⁴, R⁵ and R⁶ =H, R⁷ andR⁹ are methyl and R^(9a) =hydrogen or methyl; compounds wherein A=--CH₂--, B=--CH₂ --, R², R⁴ and R⁶ =H or methyl, R⁵, R⁹ and R^(9a) arehydrogen, and R⁷ =methyl; compounds wherein A=--CH₂ -- or --C(O)--,B=--CH₂ --, R², R⁵, R⁶, R⁹ and R^(9a) are hydrogen, R⁴ =--NH₂ and R⁷=methyl; compounds wherein A=--CH₂ --, B=--CH₂ --, R², R⁴, R⁶, R⁷, R⁹and R^(9a) are hydrogen and R⁵ =bromine; compounds wherein A=--CH₂ --,B=--CH₂ --, R², R⁴, R⁶, R⁹ and R^(9a) are hydrogen, R⁵ =fluorine,chlorine, bromine, iodine, or --NH₂, and R⁷ =hydrogen or methyl;compounds wherein A=--CH₂ -- or --CH₂ CH₂ --, B=--CH₂ --, R², R⁴, R⁵ andR⁶ are alkyl or halogen R⁷ =H or alkyl, and R⁹ and R^(9a) are alkyl;compounds wherein A=--CH₂ CH₂ --, B=--CH₂ --, R², R⁴, R⁵ and R⁶ are H orlower alkyl, R⁷ =absent or H if the pyrrolidone ring contains nounsaturation, and R⁹ and R^(9a) are H or lower alkyl.

As employed herein, "lower alkyl" refers to straight or branched chainalkyl radicals having in the range of about 1 up to 4 carbon atoms;"alkyl" refers to straight or branched chain alkyl radicals having inthe range of about 1 up to 12 carbon atoms; "substituted alkyl" refersto alkyl radicals further bearing one or more substituents such as aryl,heterocyclic, hydroxy, alkoxy (of a lower alkyl group), mercapto (of alower alkyl group), aryloxy, halogen, trifluoromethyl, cyano, nitro, aswell as:

--S(O)R', --S(O)₂ R' or --S(O)₂ NHR', wherein each R' is as definedabove, provided, however, that when R², R⁴, R⁵ or R⁶ is --S(O)R', R' isnot hydrogen, alkenyl or alkynyl, and provided that when R², R⁴, R⁵ orR⁶ is --S(O)₂ NHR'R' is not alkenyl or alkynyl;

--C(O)R", wherein R" is selected from hydrogen, alkyl, substitutedalkyl, alkoxy, alkylamino, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, aryloxy, arylamino,alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl,heterocyclic, substituted heterocyclic or trifluoromethyl, provided,however, that the carbonyl functionality is not conjugated with analkenyl or alkynyl functionality;

--OR'", wherein R'" is selected from hydrogen, alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl,substituted alkylaryl, arylalkyl, substituted arylalkyl, aroyl,substituted aroyl, heterocyclic, substituted heterocyclic, acyl,trifluoromethyl, alkylsulfonyl or arylsulfonyl, provided, however, thatthe --OR'" functionality is not conjugated with an alkenyl or alkynylfunctionality;

--NR'"₂, wherein each R'" is independently as defined above, or each R'"and the N to which they are attached can cooperate to form a 4-, 5-, 6-or 7-membered ring; provided, however, that the --NR'"₂ functionality isnot conjugated with an alkenyl or alkynyl functionality;

--SR"", wherein R"" is selected from hydrogen, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl,substituted arylalkyl, heterocyclic, substituted heterocyclic ortrifluoromethyl, provided, however, that the --SR"" functionality is notconjugated with an alkenyl or alkynyl functionality; or

--SiR'""₃, wherein R'"" is selected from alkyl or aryl; and the like;

"cycloalkyl" refers to cyclic ring-containing radicals containing in therange of about 3 up to 8 carbon atoms, and "substituted cycloalkyl"refers to cycloalkyl radicals further bearing one or more substituentsas set forth above;

"alkenyl" refers to straight or branched chain hydrocarbyl radicalshaving at least one carbon-carbon double bond, and having in the rangeof about 2 up to 12 carbon atoms and "substituted alkenyl" refers toalkenyl radicals further bearing one or more substituents as set forthabove;

"alkynyl" refers to straight or branched chain hydrocarbyl radicalshaving at least one carbon-carbon triple bond, and having in the rangeof about 2 up to 12 carbon atoms, and "substituted alkynyl" refers toalkynyl radicals further bearing one or more substituents as set forthabove;

"aryl" refers to aromatic radicals having in the range of 6 up to 14carbon atoms and "substituted aryl" refers to aryl radicals furtherbearing one or more substituents as set forth above;

"alkylaryl" refers to alkyl-substituted aryl radicals and "substitutedalkylaryl" refers to alkylaryl radicals further bearing one or moresubstituents as set forth above;

"arylalkyl" refers to aryl-substituted alkyl radicals and "substitutedarylalkyl" refers to arylalkyl radicals further bearing one or moresubstituents as set forth above;

"arylalkenyl" refers to aryl-substituted alkenyl radicals and"substituted arylalkenyl" refers to arylalkenyl radicals further bearingone or more substituents as set forth above;

"arylalkynyl" refers to aryl-substituted alkynyl radicals and"substituted arylalkynyl" refers to arylalkynyl radicals further bearingone or more substituents as set forth above;

"aroyl" refers to aryl-carbonyl species such as benzoyl and "substitutedaroyl" refers to aroyl radicals further bearing one or more substituentsas set forth above;

"heterocyclic" refers to cyclic (i.e., ring-containing) radicalscontaining one or more heteroatoms (e.g., N, O, S, or the like) as partof the ring structure, and having in the range of 3 up to 14 carbonatoms and "substituted heterocyclic" refers to heterocyclic radicalsfurther bearing one or more substituents as set forth above;

"acyl" refers to alkyl-carbonyl species; and

"halogen" refers to fluoride, chloride, bromide or iodide radicals.

In one aspect of the present invention, bridging group A is a 1, 2 or 3atom bridging species selected from alkylene, or --O--, --C(O)--,--N(R¹¹)--, and/or --S-containing alkylene moiety, wherein R¹¹ ishydrogen or a lower alkyl moiety; provided, however, that the ringformed by N⁷, C⁸, C⁹, A and B does not contain any covalentheteroatom-heteroatom single bonds, or anyheteroatom-methylene-heteroatom bonding relationships. Thus, A can beselected, for example, from --CH₂ --, --CH₂ CH₂ --, --CH₂ CH₂ CH₂ --,--C(O)--, --C(O)--CH₂ --, --C(O)--CH₂ CH₂ --, and the like. Presentlypreferred compounds of the invention are those wherein A is selectedfrom --CH₂ --, --CH₂ CH₂ -- or --C(O)--, with compounds having A as--CH₂ -- being the presently most preferred.

In accordance with another aspect of the present invention, bridginggroup B is selected from --O--, --S--, --NR¹⁰, wherein R¹⁰ is selectedfrom hydrogen, lower alkyl, aryl, substituted aryl, alkylaryl,substituted alkylaryl, arylalkyl, substituted arylalkyl; --C¹⁰ HR^(10a)--, wherein R^(10a) is selected from hydrogen, lower alkyl,hydroxyalkyl, aryl, aryloxyalkyl, fluoro, trifluoromethyl, cyano,cyanomethyl, --OR', --NR'₂, or --SR', wherein each R' is independentlyhydrogen, lower alkyl, alkenyl, alkynyl or aryl, provided, however, thatneither the --NR'₂ nor the --SR' functionality is conjugated with analkenyl or alkynyl functionality; or B is ═C¹⁰ R^(10a) -- or ═N--,provided there is no double bond in the ring between A and B, or betweenB and C⁹ when there is a double bond between N⁷ and C⁸, and providedthat B is not a heteroatom when A is a one-atom bridging species. Thus,B can be selected, for example, from --CH₂ --, --O--, --N(R¹⁰)--, --S--,and the like. Presently preferred compounds of the invention are thosewherein B is --CH₂ --.

In accordance with yet another aspect of the present invention, R^(5')is alkynyl or substituted alkynyl having the structure:

    --C.tbd.C--R.sup.5'

wherein R^(5') is selected from hydrogen, alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl,substituted alkylaryl, arylalkyl, substituted arylalkyl, heterocyclic,substituted heterocyclic, trifluoromethyl, halogen, cyano, nitro;

--S(O)R', --S(O)₂ R' or --S(O)₂ NHR', wherein each R' is as definedabove, provided, however, that when R², R⁴, R⁵ or R⁶ is --S(O)R', R' isnot hydrogen, alkenyl or alkynyl, and provided that when R², R⁴, R⁵ orR⁶ is --S(O)₂ NHR', R' is not alkenyl or alkynyl;

--C(O)R", wherein R" is selected from hydrogen, alkyl, substitutedalkyl, alkoxy, alkylamino, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, aryloxy, arylamino,alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl,heterocyclic, substituted heterocyclic or trifluoromethyl, provided,however, that the carbonyl functionality is not conjugated with analkenyl or alkynyl functionality;

--OR'", wherein R'" is selected from hydrogen, alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl,substituted alkylaryl, arylalkyl, alkylaryl, substituted arylalkyl,aroyl, substituted aroyl, heterocyclic, substituted heterocyclic, acyl,trifluoromethyl, alkylsulfonyl or arylsulfonyl, provided, however, thatthe --OR'" functionality is not conjugated with an alkenyl or alkynylfunctionality;

--NR'"₂, wherein each R'" is independently as defined above, or each R'"and the N to which they are attached can cooperate to form a 4-, 5-, 6-or 7-membered ring; provided, however, that the --NR'"₂ functionality isnot conjugated with an alkenyl or alkynyl functionality;

--SR"", wherein R"" is selected from hydrogen, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl,substituted arylalkyl, heterocyclic, substituted heterocyclic ortrifluoromethyl, provided, however, that the --SR"" functionality is notconjugated with an alkenyl or alkynyl functionality; or

--SiR'""₃, wherein R'"" is selected from alkyl or aryl, and the like.

In addition, R^(5') can also be alkylene, substituted alkylene, arylene,substituted arylene, and the like, so that the resulting compound is apolyfunctional species, bearing two or more of the substituted pyridylstructures contemplated by structure I. Thus, R⁵ serves as a bridge orlinking moiety to couple two or more of the substituted pyridylstructures contemplated by structure I in a single compound.

Presently preferred R^(5') groups include hydrogen, methyl, ethyl,propyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxymethyl,2-hydroxy-2-isopropyl, dimethylaminomethyl, phenyl, and the like.

Additional preferred compounds of the invention are those wherein R² isselected from hydrogen or amino; wherein R⁴ is hydrogen, aryl, alkoxy oraryloxy; wherein R⁵ is selected from aryl, substituted aryl (whereinsubstituents on the aryl ring are independently selected from one ormore of bromine, chlorine, fluorine, phenyl, methoxy, hydroxy,mercaptomethyl and trifluoromethyl substituents being especiallypreferred), trialkylsilyl, arylalkyl, arylalkenyl or arylalkynyl;wherein R⁶ is selected from hydrogen, chlorine, amino, alkyl or alkoxy(with hydrogen, methyl or methoxy being especially preferred); whereinR⁷ is absent or selected from hydrogen or methyl; and wherein R⁹ andR^(9a) are each independently selected from hydrogen, lower alkyl,alkoxy or aryloxy.

Particularly preferred compounds of the invention include the compoundwherein A=--CH₂ -- or --CH₂ CH₂ --, B=--CH₂ --, R² =H, R⁴ =H, R⁵ isselected from ethynyl, methylethynyl, ethylethynyl, propylethynyl,hydroxymethylethynyl, 1-hydroxyethylethynyl, 2-hydroxyethylethynyl ,methoxymethylethynyl, 2-hydroxy-2-propylethynyl,dimethylaminomethylethynyl, 3-chloro-4-hydroxyphenyl, 3-chlorophenyl,3-fluoro-4-methoxyphenyl, 4-hydroxyphenyl, 4-biphenyl, phenylethynyl,4-methoxyphenyl, 4-fluorophenyl, 3-fluoro-4-hydroxyphenyl,4-methylphenyl, 3-chloro-4-methoxyphenyl, 4-aminophenyl,4-acetamidophenyl, 4-acetoxyphenyl, 3-chloro-4-acetoxyphenyl,3-chloro-4-acetamidophenyl, 4-methanesulfonanilido,or3-chloro-4-methanesulfonanilido, R⁶ =H, R⁷ =H, methyl, or R⁷ is absentwhen there is a double bond between N⁷ and C⁸, R⁹ =H, and R^(9a) =H.

Invention compounds have affinity for acetylcholine receptors. Asemployed herein, the term "acetylcholine receptor" refers to bothnicotinic and muscarinic acetylcholine receptors. Affinity of inventioncompounds for such receptors can be demonstrated in a variety of ways,e.g., via competitive radioligand binding experiments in which the testcompounds displace isotopically labelled ligands (such as nicotine,cytisine, methylcarbamylcholine, quinuclidinyl benzilate, and the like)from binding sites in mammalian cerebral membranes. Furthermore, thebinding of compounds to acetylcholine receptors can be evaluated as afunctional response. For example, the activity of invention compoundscan be evaluated employing functional assays based on recombinantneuronal acetylcholine receptor expression systems (see, for example,Williams et al., Drug News & Perspectives 7:205-223 (1994)). Testcompounds can also be evaluated for their ability to modulate therelease of neurotransmitters (e.g., dopamine, norepinephrine, and thelike) from rat brain slices (e.g., striatum, hippocampus, and the like).See Examples 24 and 25 for further detail on such techniques. Moreover,test compounds can also be evaluated by way of behavioral studiesemploying animal models of various CNS, autonomic and cardiovasculardisorders (see, for example, D'Amour and Smith, J. Pharmacol. Exp. Ther.72:74-79 (1941) and Iwamoto, J. Pharmacol. Exp. Ther. 251:412-421 (1989)for animal models of pain; Klockgether and Turski, Ann. Neurol.28:539-546 (1990), Colpaert, F., Neuropharmacology 26:1431-1440 (1987),Ungerstedt and Arbuthknott, Brain Res. 24:485-493 (1970), VonVoigtlander and Moore, Neuropharmacology 12:451-462 (1973), Ungerstedtet al., Adv. Neurol. 3:257-279 (1973), Albanese et al., Neuroscience55:823-832 (1993), Janson et al., Clin. Investig. 70:232-238 (1992),Sundstrom et al., Brain Res. 528:181-188 (1990), Sershen et al.,Pharmacol. Biochem. Behav. 28:299-303 (1987) for animal models ofParkinson's disease; Williams et al., Gastroenterology 94:611-621(1988), Miyata et al., J. Pharmacol. Exp. Ther. 261:297-303 (1992),Yamada et al., Jpn. J. Pharmacol. 58 (Suppl.):131 (1992) for animalmodels of irritable bowel syndrome; Coyle et al., Neurobehav. Toxicol.Tetatol. 5:617-624 (1983), Schartz et al., Science 219:316-318 (1983)for animal models of Huntington's disease; Clow et al., Euro. J.Pharmacol. 57:365-375 (1979), Christensen et al., Psychoparmacol. 48:1-6(1976), Rupniak et al., Psychopharmacol. 79:226-230 (1983), Waddingtonet al., Science 220:530-532 (1983) for animal models of tardivedyskinesia; Emerich et al., Pharmacol. Biochem. Behav. 38:875-880 (1991)for animal models of Gilles de la Tourette's syndrome; Brioni et al.,Eur. J. Pharmacol. 238:1-8 (1993), Pellow et al., J. Neurosci. Meth.14:149 (1985) for animal models of anxiety; and Estrella et al., Br. J.Pharmacol 93:759-768 (1988) for the rat phrenic nerve model whichindicates whether a compound has muscle effects that may be useful intreating neuromuscular disorders).

Those of skill in the art recognize that invention compounds typicallycontain one or more chiral centers, and thus can exist as racemicmixtures. For many applications, it is preferred to carry outstereoselective syntheses and/or to subject the reaction product toappropriate purification steps so as to produce substantially opticallypure materials. Suitable stereoselective synthetic procedures forproducing optically pure materials are well known in the art, as areprocedures for purifying racemic mixtures into optically pure fractions.

In accordance with still another embodiment of the present invention,there are provided methods for the preparation of pyridine compounds asdescribed above. For example, many of the pyridine compounds describedabove can be prepared using synthetic chemistry techniques well known inthe art from the acyl pyridine precursor of Formula II as outlined inScheme I. ##STR2##

In the above scheme, R², R⁴, R⁵, R⁶, R⁷, R⁹, R^(9a), A and B are asdefined above, P is a nitrogen protecting group, and X is a carboxylicacid activating group. Nitrogen protecting groups contemplated for useherein are functional groups which are stable under basic conditions,but which are readily removed under acidic conditions. Examples ofsuitable protecting groups include vinyl groups, tert-butylcarbonylgroups, benzyloxycarbonyl groups, formyl groups, and the like.Carboxylic acid activating groups, X, contemplated for use herein can bereadily identified by those of skill in the art, and include esters,acid chlorides, mixed anhydrides, the Weinreb amide, and the like.

In step A of Scheme I, acyl pyridine of Formula II is coupled in thepresence of strong base with a lactam of Formula III to produce apyridoyllactam of Formula IV. The choice of base for use in thiscoupling reaction depends, at least in part, on the acidity of thehydrogen atoms adjacent to the carbonyl group of compound III. Ingeneral, strong bases such as sodium hydride, sodamide, lithiumdiisopropylamide, lithium hexamethyldisilazide, and the like, are used.The presently preferred base for use in the practice of the presentinvention is lithium hexamethyldisilazide.

The above-described coupling reaction is typically carried out inaprotic solvent, such as, for example, tetrahydrofuran (THF), diethylether, tert-butyl methyl ether, 1,2-dimethoxyethane, toluene, and thelike. Presently preferred solvents for use in the practice of thepresent invention are THF and tert-butyl methyl ether. The couplingreaction can be carried out over a wide range of temperatures. Typicallyreaction temperatures fall in the range of about -78° C. up to reflux.Temperatures in the range of about -78° C. up to ambient are presentlypreferred. Reaction times required to effect the desired couplingreaction can vary widely, typically falling in the range of about 15minutes up to about 24 hours. Preferred reaction times fall in the rangeof about 4 up to 12 hours. It is not necessary to purify the product ofthe above-described coupling reaction (i.e., compound of Formula IV),and the resulting reaction product is typically subjected directly tothe rearrangement step described below as step B.

In Step B of Scheme I, pyridoyllactam of Formula IV is rearranged toproduce the cyclic imine V. Concomitantly with this rearrangement,protective group P is removed (although, if desired, the protectinggroup can be selectively removed from compound IV prior to therearrangement). The desired rearrangement is typically effected bycontacting pyridoyllactam with aqueous media containing strong acid(e.g., hydrochloric acid, hydrobromic acid, sulfuric acid,trifluoroacetic acid, and the like) under reflux conditions. Presentlypreferred media for the above-described rearrangement reaction is 19%aqueous hydrochloric acid. The desired rearrangement reaction istypically complete within about 1 up to 24 hours, with 4 up to 12 hoursgenerally being sufficient.

Cyclic imine of Formula V can then be recovered from the reaction mediaby basification, followed by extraction, filtration, and the like.Purification can be achieved by a variety of techniques, such as, forexample, chromatography, recrystallization, and the like.

Conversion of cyclic imine V into compounds of the invention (as definedby structure I) can be accomplished employing numerous syntheticprocedures, such as, for example, the procedures set forth is steps Cand D of Scheme I. Thus, as shown in Step C, cyclic imine V is convertedinto cyclic amine VI by reduction of the imine. This reduction reactioncan be promoted, for example, by hydride addition, employing a suitablehydride source (e.g., sodium borohydride, sodium cyanoborohydride,lithium aluminum hydride, sodium triacetoxyborohydride, lithiumtri-tert-butoxy aluminum hydride, sodium trimethoxyborohydride,diisobutylaluminum hydride, formic acid, and the like) or by contactingthe imine with hydrogen in the presence of a transition metal catalyst(such as, for example, palladium on carbon, Raney Nickel, platinumoxide, tris(triphenylphosphine)rhodium (I) chloride (i.e., Wilkinson'scatalyst), palladium hydroxide, and the like). Presently preferredreducing conditions comprise treating imine V with sodium borohydride ina solvent mixture such as methanol/acetic acid, at a reactiontemperature in the range of about -60° C. up to about ambienttemperature, for in the range of about 1 up to 24 hours. As recognizedby those of skill in the art, the selection of reducing agent, reactiontime, reaction temperature and reaction media will depend on thespecific compound having the Formula V which is being treated.

Cyclic amine VI can be isolated from the reaction mixture employingstandard separation techniques which are well known to those of skill inthe art. Similarly, purification of amine can be achieved employingstandard purification techniques, such as, for example, chromatography,recrystallization, distillation, and the like. If desired, cyclic amineVI can be further converted into an acid addition salt.

Since cyclic amine VI has a center of asymmetry, reagents for theabove-described reduction reaction can be chosen so as to promoteselective reduction to produce amine VI which is substantially enrichedin one of the possible enantiomers. In some instances, by judiciouschoice of reducing agents, each of the possible enantiomers can beprepared in high optical purity. For example, chiral borohydridereducing agents can be employed, as described, for example, by Yamada etal. in J. Chem. Soc., Perk. 1 265 (1983), Kawate et al., in TetrahedronAsym. 3, 227 (1992), Mathre et al., J. Org. Chem. 58:2880 (1993), or choand Chun in J. Chem. Soc. Perk. 1 3200 (1990). Alternatively, catalytichydrogenation in the presence of chiral catalyst can be employed, asdescribed, for example, by Kitamura et al., in J. Org. Chem. 59:297(1994), Burk et al., in Tetrahedron 50:4399 (1994), Burk et al, in J.Am. Chem. Soc. 115:10125 (1993), Willoughby and Buchwald in J. Org.Chem. 58:7627 (1993), or Willoughby and Buchwald in J. Am. Chem. Soc.114:7562 (1992). As yet another alternative, optically pure enantiomersof compounds of Formula I can be prepared by resolution of a mixture ofenantiomers by selective crystallization of a single enantiomer in thepresence of an optically pure acid addition salt. Such methods are wellknown in the art, such as, for example, the preparation of opticallypure addition salts with each isomer of tartaric acid, tartaric acidderivatives (e.g., D- or L-dibenzoyl and di-p-tolyl-tartaric acid, andthe like. Another method which is widely used in the art involves thepreparation of diastereomeric derivatives of racemic amines (e.g.,α-methoxy-α-(trifluoromethyl)phenylacetic acid (i.e., Mosher's acid)amide derivatives). The resulting diastereomeric derivatives can then beseparated by well known techniques, such as chromatography.

The separation of the respective enantiomers of a racemic mixture can beaccomplished employing chromatographic techniques which utilize a chiralstationary phase. Examples include chiral gas chromatography (chiralGC), chiral medium performance liquid chromatography (chiral MPLC),chiral high performance liquid chromatography (chiral HPLC), and thelike.

For compounds of Formula I, where R⁷ is not hydrogen, alkylation step Dof Scheme I is carried out. Those of skill in the art can readilyidentify suitable N-alkylation reactions suitable for such purpose. Forexample, cyclic amine of Formula VI can be contacted with an aldehyde(e.g., formaldehyde, acetaldehyde, benzaldehyde, and the like) in thepresence of a suitable reducing agent (such as the reducing agentsdescribed above with reference to Step C).

The substituted amines of Formula I produced by the above-describedalkylation/reduction reaction can be isolated and purified employingstandard methods which are well known in the art (e.g., extraction,chromatography, and the like). A presently preferred technique forrecovery of reaction product is extraction of amine I from basifiedreaction medium with dichloromethane. Alternatively, crude amine can beconverted into an acid addition salt (e.g., hydrochloride, hydrobromide,fumarate, tartrate, and the like), then purified by recrystallization.

Where R⁷ of Formula I is a methyl group, it is possible to carry out thesteps set forth in Scheme I wherein protecting group P is methyl (see,for example, Spath & Bretschneider in Chem. Ber. 61:327 (1928)).

Another method for the preparation of compounds of Formula I is depictedin Scheme II, ##STR3##

In the above scheme, Y is an active functionality which is capable ofundergoing a transition metal catalyzed coupling reaction. Examples of Yinclude bromine, iodine, trifluoromethylsulfonyloxy, and the like. InStep A of Reaction Scheme II, a coupling reaction is carried out,typically promoted by an organometallic coupling catalyst. A presentlypreferred method for carrying out the desired coupling reaction is tometallate furan VIII with a suitable organometallic reagent (e.g.,tert-butyllithium followed by zinc chloride, tributyltin chloride,trimethyltin chloride, triisopropylborate, and the like), followed bycoupling of the metallated species with pyridine derivative VII in thepresence of a transition metal catalyst (e.g., PdCl₂ (PPh₃)₂) in asuitable solvent (e.g., ether or THF).

The coupling reaction is typically allowed to proceed by allowing thereaction temperature to warm slowly from about -78° C. up to ambienttemperature over a period of several hours. The reaction mixture is thenmaintained at ambient temperature for a time in the range of about 4 upto 24 hours, with about 12 hours typically being sufficient.

The coupling product, pyridylfuran IX, can be isolated and purifiedemploying standard techniques, such as solvent extraction,chromatography, crystallization, distillation, and the like.

Conversion of pyridylfuran IX to the pyridylpyrrolidine of Formula I(wherein A and B each are CH₂ and R⁹ and R^(9a) are each H) can beachieved in a two-step process, as illustrated in Steps B and C ofScheme II. Thus, in Step B, the furan group is hydrolyzed by contactingpyridylfuran IX with aqueous media containing a strong acid (e.g.,sulfuric acid) under reflux conditions for a time in the range of about1 up to 48 hours. The resulting dicarbonyl compound of Formula X canthen be cyclized to the pyrrolidine of Formula I by treatment with asuitable amine, such as R⁷ NH₂. Amination/ring formation contemplated byStep C of Scheme II is typically carried out in the presence of asuitable reducing agent (such as described above with reference toScheme I, Step C).

As is known in the art, cyclization of dicarbonyl compound X can becarried out under conditions which promote stereoselective ringformation, thereby producing substantially optically pure products. See,for example, Manescalchi, Nardi and Savoia in Tetrahedron Letters35:2775 (1994).

When any one or more of R², R⁴, R⁵ or R⁶ of compounds of Formula I arereactive substituents (e.g., bromine, iodine,trifluoromethylsulfonyloxy, and the like), it is possible to furthermodify such compounds taking advantage of the presence of the reactivefunctionality. One such modification is shown in Scheme III. ##STR4##

In Scheme III, the starting material employed is a compound of theFormula I, wherein Y is as defined above. If R⁵ in the desired finalproduct is an aryl or substituted aryl group, such products can beprepared employing well known organometallic procedures, such as, forexample, by coupling with an arylzinc compound (prepared by reaction ofan arylbromide with an alkyllithium reagent such as n-butyllithium ortert-butyllithium, followed by addition of zinc chloride) with compoundof Formula I, wherein Y is as defined above, in the presence of acatalytic amount of a suitable coupling catalyst (e.g., PdCl₂ (PPh₃)₂,and the like) in a suitable solvent such as toluene, dimethylformamide,THF, and the like. Suitable reaction temperatures fall in the range ofabout 0° C. to 140° C. (with temperatures in the range of about 0° C. upto 80° C. being preferred), with reaction times in the range of about 4up to 24 hours.

Similarly, coupling procedures can be used to prepare compounds ofFormula I in which R², R⁴, R⁵ and R⁶ are independently alkyl, alkenyl,alkynyl, arylalkyl, alkylaryl, and the like. An alternative method topromote the desired coupling reaction employs organoborane chemistry,wherein arylboronic acids, in the presence of a suitable catalyst (e.g.,Pd(Ph₃)₄) in basic aqueous dimethoxyethane are coupled with compounds ofFormula I wherein one or more of R², R⁴, R⁵ and R⁶ is Y. The reaction istypically carried out at a temperature in the range of about 40° C. upto 150° C. (with a temperature in the range of 80° C. being preferred),for a time in the range of about 1 up to 24 hours (with about 8 hoursbeing preferred). Arylboronic acids are well known in the art and can bereadily obtained by those of skill in the art.

Yet another method for the preparation of compounds of Formula I isdescribed in Scheme IV. ##STR5##

In Scheme IV, Q represents a protecting group that enhances the acidityof the adjacent hydrogen atom, and X and Z are leaving groups (such ashalogen). An example of Q is is the tert-butyloxycarbonyl group. GroupsX and Z are independently selected from I, Br or Cl. It is preferredthat in X is Br, then Z is I, or, alternatively, if X is Cl, Z is Br orI.

In Step A of Scheme IV, the protected pyridylamine of Formula XI isalkylated with alkylating moiety XII. This reaction proceeds in thepresence of a strong base (e.g., sodium hydride, lithiumhexamethyldisilazide, lithium diisopropylamide, and the like) in polaraprotic solvent (e.g., THF, diethyl ether, tert-butyl methyl ether, andthe like). Reaction is typically carried out at a temperature in therange of about -78° C. up to 100° C., where the actual temperatureemployed varies depending on the nature of X, Z and the substituents onXII. Typically, the reaction is carried out at ambient temperature for aperiod of time ranging from about 1 to 24 hours.

The resulting alkylated pyridylamine of Formula XIII can then beisolated and purified using techniques known in the art such asextraction with an organic solvent and concentration, followed bychromatography, recrystallization, and the like.

The ring forming cyclization contemplated by Step C is promoted bystrong base (e.g., alkyllithiums, sec-butyllithium, tert-butyllithium,and the like). Reaction is carried out in suitable solvent (e.g., THF,diethyl ether, tert-butyl methyl ether, and the like), initially at lowtemperature (e.g., -78° C.), then allowed to warm gradually to ambienttemperature. Reaction time varies as a function of the substituentspresent on the reacting species. Generally, where R⁹ is a large (bulky)group, longer reaction times will be required. Typical reaction timesfall in the range of about 1 up to 24 hours, with 4 hours generallybeing sufficient.

The resulting protected cyclic amine of Formula XIV can be isolated andpurified by standard techniques well known by those of skill in the art,e.g., chromatographic techniques such as flash chromatography.

The deprotection reaction depicted in Step C can be carried out usingtechniques known in the art. This deprotection reaction is typicallyachieved by acid treatment (e.g., employing trifluoroacetic acid orhydrogen chloride in a suitable solvent such as diethyl ether). Theresulting cyclic amine can then be isolated and purified by well knownprocedures, as described above.

In another example, compounds of Formula I in which R₇ is hydrogen canbe prepared using methodology depicted in Scheme V. See, for example,Nilsson and Hallberg in J. Org. Chem. 55:2464 (1990). ##STR6##

Step A of Scheme V is an organometallic catalyzed coupling reaction(also known as the Heck reaction). Typically, a pyridine of Formula VIIis contacted with a protected, cyclic enamine of Formula XV in thepresence of Pd(OAc)₂ and triethylamine in a suitable solvent. Thereaction temperature typically falls in the range of about 0° C. up to140° C. (with a temperature of about 80° C. being preferred). Reactiontime can vary widely, typically falling in the range of about 8 hours upto several days (with at least about 24 hours generally being requiredto allow the coupling reaction to go to completion).

The resulting unsaturated cyclic amine of Formula XVI can then beisolated and purified employing standard techniques (e.g., distillation,chromatography, and the like).

If enantiomerically enriched compound of Formula XVI is desired,asymmetric Heck reactions, which are well known in the art, can beemployed. Thus, a chiral catalyst (e.g., (R)-BINAP, i.e., the (R)configuration of 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) can beused to induce the formation of chiral product. See, for example, Ozawa,Kobatake and Hayashi in Tetrahedron Letters 34:2507 (1993).

Conversion of the unsaturated, protected cyclic amine to compounds ofFormula I can be achieved in a single step, as illustrated in Step B.Thus, catalytic hydrogenation in the presence of a suitable catalyst(e.g., PtO₂, Pd/C, and the like), in a suitable solvent (e.g., ethanol,acetic acid, and the like), provides compounds of Formula I.Alternatively, sequential deprotection, followed by reduction can becarried out (employing methods described above with respect to Scheme I,Step C).

Another procedure which can be used to prepare compounds embraced byFormula I is set forth in Scheme VI below. ##STR7##

In the above scheme, Tf represents the trifluoromethylsulfonyl group. InStep A, pyridines of Formula VII are coupled with an enol triflate ofFormula XVII in the presence of a suitable organometallic catalyst(e.g., PdDBA, Pd(PPh₃)₄, PdCl₂ (PPh₃)₂, and the like),triphenylphosphine or triphenylarsine, and lithium chloride in anaprotic solvent (e.g., dimethylformamide, THF, dimethoxyethane,N-methylpyrrolidone, and the like). Reaction temperatures typically fallin the range of about 0° C. up to 140° C. (with about 80° C. beingpreferred). Reaction times generally fall in the range of about 4 up to72 hours (with about 12 hours generally being sufficient). The couplingreaction product can then be isolated and purified employing standardtechniques (e.g., extraction, chromatography, recrystallization, and thelike).

In Step B, catalytic hydrogenation of compound of Formula XVIII in thepresence of suitable hydrogenation catalyst (e.g., Pd/C, PtO₂, and thelike) simultaneously saturates the double bond in XVIII, and removes thebenzyloxycarbonyl protecting group, thereby producing compounds ofFormula I. As noted above, asymmetric hydrogenation techniques can beemployed in Step B to afford substantially optically pure compounds ofFormula I.

Another synthetic strategy which can be employed for the preparation ofcompounds of Formula I is presented in Scheme VII. See, for example,Huang, Chu and Fowler in J. Org. Chem. 1985 50:3885. ##STR8##

In Step A of Scheme VII, the lithium derivative of pyridine VII iscoupled with lactam XIX. This coupling reaction is carried out in anaprotic solvent as follows. Pyridine VII in suitable solvent (e.g.,diethyl ether) is contacted with an alkyllithium (e.g.,tert-butyllithium) at a temperature in the range of about -78° C. up to0° C. Lactam XIX is then added to the reaction mixture and the couplingreaction allowed to proceed for a time in the range of about 15 minutesup to about 8 hours. The reaction mixture is then neutralized andalcohol XX recovered by solvent extraction.

In Step B, the alcohol group of compound XX is removed by reductionthereof. While hydride reduction or hydrogenation conditions can beemployed, the choice of reduction conditions is based, at least in part,on the chemical nature of the substituents on compound XX. For example,alcohol XX can be treated with lithium aluminum hydride in ether for1-12 hours at temperatures in the range of about 20° C. up to reflux.Alternatively, alcohol XX can be dissolved in a suitable solvent (e.g.,ethanol, acetic acid, and the like) and then exposed to hydrogen underhydrogenation conditions in the presence of a suitable catalyst (e.g.,Pd/C, PtO₂, and the like). Hydrogenation conditions typically compriseambient temperature at pressures in the range of about 1-10 atmospheresof hydrogen (with 2-3 atmospheres being preferred).

In addition to the above-described synthetic procedures, those of skillin the art have access to numerous other synthetic procedures which canbe employed for the preparation of invention compounds. Indeed, theliterature is replete with methodologies useful for the preparation ofthe basic nicotine and anabasine nuclei, which can then be modified tointroduce the necessary substituents to satisfy the requirements ofFormula I.

In accordance with another embodiment of the present invention, thereare provided pharmaceutical compositions comprising pyridine compoundsas described above, in combination with pharmaceutically acceptablecarriers. Optionally, invention compounds can be converted intonon-toxic acid addition salts, depending on the substituents thereon.Thus, the above-described compounds (optionally in combination withpharmaceutically acceptable carriers) can be used in the manufacture ofa medicament for modulating the activity of acetylcholine receptors.

Pharmaceutically acceptable carriers contemplated for use in thepractice of the present invention include carriers suitable for oral,intravenous, subcutaneous, transcutaneous, intramuscular,intracutaneous, inhalation, and the like administration. Administrationin the form of creams, lotions, tablets, dispersible powders, granules,syrups, elixirs, sterile aqueous or non-aqueous solutions, suspensionsor emulsions, patches, and the like, is contemplated.

For the preparation of oral liquids, suitable carriers includeemulsions, solutions, suspensions, syrups, and the like, optionallycontaining additives such as wetting agents, emulsifying and suspendingagents, sweetening, flavoring and perfuming agents, and the like.

For the preparation of fluids for parenteral administration, suitablecarriers include sterile aqueous or non-aqueous solutions, suspensions,or emulsions. Examples of non-aqueous solvents or vehicles are propyleneglycol, polyethylene glycol, vegetable oils, such as olive oil and cornoil, gelatin, and injectable organic esters such as ethyl oleate. Suchdosage forms may also contain adjuvants such as preserving, wetting,emulsifying, and dispersing agents. They may be sterilized, for example,by filtration through a bacteria-retaining filter, by incorporatingsterilizing agents into the compositions, by irradiating thecompositions, or by heating the compositions. They can also bemanufactured in the form of sterile water, or some other sterileinjectable medium immediately before use.

Invention compounds can optionally be converted into non-toxic acidaddition salts. Such salts are generally prepared by reacting thecompounds of this invention with a suitable organic or inorganic acid.Representative salts include the hydrochloride, hydrobromide, sulfate,bisulfate, methanesulfonate, acetate, oxalate, valerate, oleate,laurate, borate, benzoate, lactate, phosphate, tosylate, citrate,maleate, fumarate, succinate, tartrate, napsylate, and the like. Suchsalts can readily be prepared employing methods well known in the art.

In accordance with yet another embodiment of the present invention,there are provided methods of modulating the activity of acetylcholinereceptors, said method comprising:

contacting cell-associated acetylcholine receptors with a concentrationof a pyridine compound as described above sufficient to modulate theactivity of said acetylcholine receptors.

As employed herein, the phrase "modulating the activity of acetylcholinereceptors" refers to a variety of therapeutic applications, such as thetreatment of Alzheimer's disease and other disorders involving memoryloss and/or dementia (including AIDS dementia); cognitive dysfunction(including disorders of attention, focus and concentration), disordersof extrapyramidal motor function such as Parkinson's disease,progressive supramuscular palsy, Huntington's disease, Gilles de laTourette syndrome and tardive dyskinesia; mood and emotional disorderssuch as depression, panic, anxiety and psychosis; substance abuseincluding withdrawal syndromes and substitution therapy; neuroendocrinedisorders and dysregulation of food intake, including bulemia andanorexia; disorders of nociception and control of pain; autonomicdisorders including dysfunction of gastrointestinal motility andfunction such as inflammatory bowel disease, irritable bowel syndrome,diarrhea, constipation, gastric acid secretion and ulcers;pheochromocytoma; cardiovascular dysfunction including hypertension andcardiac arrhythmias, comedication in surgical procedures, and the like.

The compounds of the present invention are especially useful for thetreatment of Alzheimer's disease as well as other types of dementia(including dementia associated with AIDS), Parkinson's disease,cognitive dysfunction (including disorders of attention, focus andconcentration), attention deficit syndrome, affective disorders, and forthe control of pain. Thus modulation of the activity of acetylcholinereceptors present on or within the cells of a patient suffering from anyof the above-described indications will impart a therapeutic effect.

As employed herein, the phrase "an effective amount", when used inreference to compounds of the invention, refers to doses of compoundsufficient to provide circulating concentrations high enough to impart abeneficial effect on the recipient thereof. Such levels typically fallin the range of about 0.001 up to 100 mg/kg/day; with levels in therange of about 0.05 up to 10 mg/kg/day being preferred.

The invention will now be described in greater detail by reference tothe following non-limiting examples.

EXAMPLE 1 Ethyl 5-bromo-3-pyridinecarboxylate

To a slurry of 5-bromo-3-pyridinecarboxylic acid (100.0 g, 0.495 mol) in1,2-dichloroethane (200 mL), thionyl chloride (108 mL, 1.485 mmol) wasslowly added over a period of 30 min with intermittent cooling in an icebath to maintain a temperature below 20° C. The reaction mixture wasallowed to warm to room temperature, and heated to reflux for 18 h. Thereaction mixture was cooled to 10° C., and additional thionyl chloride(14.7 g, 0.12 mmol) was added dropwise. The reaction was warmed toreflux for 6 h, then allowed to cool to room temperature. Residualthionyl chloride and solvent were removed by rotary evaporation followedby high vaccum to provide 5-bromo-3-pyridinecarbacyl chloridehydrochloride as a colorless solid (128 g, 101%).

To a suspension of 5-bromo-3-pyridinecarbacyl chloride (98.5 g , 0.39mmol) in 1,2-dichloromethane at 0° C. absolute ethanol (50 mL) was addeddropwise over period of 1.5 h. The resulting clear solution was stirredat room temperature for 2 h and the unreacted ethanol and solvent wereremoved by rotary evaporation followed by high vacuum. The off-whitesolid remaining was dissolved in 1N aqueous hydrochloric acid and washedwith three 75 mL portions of dichloromethane. The aqueous phase wasadjusted to pH 12 by the addition of solid sodium hydroxide andextracted three times with 75 mL portions of dichloromethane. Thecombined organic phases from the basic extraction were treated withmagnesium sulfate and activated charcoal,and filtered through Celite™.Heptane (250 mL) was added and the pale yellow solution of crude productwas concentrated to 300 mL by rotary evaporation then slowly cooled to-20° C. to induce crystallization. An initial crop of colorless crystals(51.5 g) was collected. Several further crops were produced byconcentration of the remaining mother liquors which after furtherpurification by fractional crystallization from heptane providedadditional product (18.9 g). The purified later crops were combined withthe the initial crop to provide ethyl 5-bromo-3-pyridinecarboxylate(70.4 g, net 78%) as a colorless crystalline solid. M.p. 40°-41° C.(heptane); ¹ HNMR (CDCl₃, 300 MHz) δ 9.13 (d, J=1.8 Hz, 1H), 8.84 (d,J=2.3 Hz, 1H), 8.44 (t, J=2.0 Hz, 1H), 4.43 (q, J=7.2 Hz, 2 H), 1.42 (t,J=7.2 Hz, 3H).

EXAMPLE 2 5-Bromo-3-(2-pyrrolin-1-yl)pyridine

A mixture of lithium bis(trimethylsilyl)amide (300 mL of a 1M solutionin THF, 300 mmol) and t-butyl methyl ether (250 mL) under inertatmosphere was cooled to -50° C. (internal temperature) andN-vinylpyrrolidinone (32 mL, 300 mmol) was added. Stirring was continuedfor 30 minutes at -50° C. and ethyl 5-bromo-3-pyridinecarboxylate (44.5g, 193 mmol) in t-butyl methyl ether (100 mL) was added. The reactionmixture was allowed to warm to 25° C. and stirred for 18 h beforequenching the reaction with a mixture acetic acid (20 mL) and methanol(20 mL). The solvents were removed in vacuo, water (100 mL) andconcentrated HCl (100 mL) were added and the mixture heated under refluxfor 18 h.

The reaction flask was cooled to 0° C. and basified with sodiumhydroxide solution (60 g in 250 mL water) and extracted withdichloromethane (3×200 mL). The combined organic extracts were washedwith brine (100 mL), dried (MgSO₄) and concentrated in vacuo. Theresidue was dissolved in the minimum amount of dichloromethane andfiltered through a pad of silica gel with ethyl acetate as the eluant.The filtrate was concentrated in vacuo and the solid which crystallizedout during this process was collected, washed with ethyl acetate anddried to afford 5-bromo-3-(2-pyrrolin-1-yl)pyridine (26 g, 60%) as asolid.

M.p. 98°-99° C. (EtOAc); ¹ H NMR (CDCl₃, 300 MHz) δ 8.88 (s, 1H), 8.71(s, 1H), 8.35 (d, J=2 Hz, 1H), 4.10 (td, J=8, 2 Hz, 2H), 2.94 (td, J=8,2 Hz, 1H), 2.09 (quintet, J=8 Hz, 2H).

EXAMPLE 3 5-Bromo-3-(2-pyrrolidinyl)pyridine

To a stirred slurry of 5-bromo-3-(2-pyrrolin-1-yl)pyridine (23.25 g,0.103 mol) in 8:2 methanol:acetic acid (250 mL) at -78° C. under inertatmosphere was slowly added solid sodium borohydride (1.96 g, 0.052 mol)in several portions over 1.5 h so as to maintain an internal temperaturebelow -60° C. The reaction mixture was allowed to warm to 0° C. andstirred for 3 h, followed by an additional 17 h at room temperature.

The reaction mixture was diluted with 75 mL of water and the organicsolvents were removed by rotary evaporation to leave an orange solutionwhich was then diluted with water to 300 mL providing a solution of pH3.5. The acidic solution was washed 4 times with 75 mL portions ofmethylene chloride, the pH of the aqueous phase was adjusted to 12 withsolid sodium hydroxide, then extracted twice with 100 mL portions ofchloroform. The combined chloroform fractions were treated withmagnesium sulfate and activated charcoal, filtered through Celite™, andthe solvent was removed by rotary evaporation followed high vacuum.5-Bromo-3-(2-pyrrolidinyl)pyridine (20.34 g, 88%) was obtained as a paleyellow oil. LRMS (EI) m/e 227 (C₉ H₁₁ N₂ ⁸¹ Br--H⁺), 225 (C₉ H₁₁ N₂ ⁷⁹Br--, H⁺); ¹ H NMR (DMSO-d₆, 300 MHz) δ 8.53 (d, J=2.2 Hz, 1H), 8.49 (d,J=1.8 Hz, 1H), 7.91 (t, J=2.0 Hz, 1H), 4.17 (t, J=7.7 Hz, 1H), 3.18 (m,1H), 3.06 (m, 1H), 2.00 (m, 1H), 2.07 (s, 1H), 2.00-1.77 (m, 2H), 1.63(m, 1H).

EXAMPLE 4 5-Bromo-3-(1-methyl-2-pyrrolidinyl)pyridine

To a solution of 5-bromo-3-(2-pyrrolidinyl) pyridine (18.14 g, 80.6mmol) in acetonitrile (250 mL) at a temperature of 0° C. was added anaqueous solution of formaldehyde (60.4 mL, 37% by weight, 806 mmol) andthe mixture was stirred for 20 min. Solid sodium cyanoborohydride (7.60g, 120 mmol) was added in several portions over 30 min, and the reactionmixture was stirred at 0° C. for an additional 90 min, then 3.0 mL ofacetic acid was added and the reaction was allowed to warm to roomtemperature and stirred for 15 h.

The reaction mixture was diluted with 75 mL of 1M aqueous hydrochloricacid and the organic solvents were removed by rotary evaporation. Theresidue was adjusted to pH 2.5 by the addition of 1N HCl and extractedthree times with 75 mL portions of methylene chloride. The aqueous phasewas basified to pH 12 by the addition of solid sodium hydroxide andextracted three times with 75 mL portions of methylene chloride. Theorganic phases from the basic extraction were combined and treated withmagnesium sulfate and activated charcoal, then filtered through Celite™.The solvent was removed by rotary evaporation, and the residual solventwas removed under high vacuum to provide 5-bromo-3(1-methyl-2-pyrrolidinyl)pyridine (18.19 g, 95%) as a pale yellow oil.LRMS (EI) m/e 242 (C₁₀ H₁₃ N₂ ⁸¹ Br), 241 (C₁₀ H₁₃ N₂ ⁷⁹ Br--⁺ H), 240(C₁₀ H₁₃ N₂ ⁷⁹ Br), 239 (C₁₀ H₁₃ N₂ ⁷⁹ Br--⁺ H); ¹ H NMR (DMSO-d₆, 300MHz) δ 8.55 (d, J=2.1 Hz, 1H), 8.44 (d, J=1.9 Hz, 1H), 7.88 (t, J=1.9Hz, 1H), 3.24 (bd-t, J=8.1 Hz, 1H), 3.10 (t, J=8.0 Hz, 1H), 2.36 (m,1H), 2.18 (s, 3H), 1.95 (m, 1H), 1.85 (m, 1H), 1.70 (m, 1H).

EXAMPLE 5 5-Bromo-3-(2-piperidein-1-yl)pyridine

δ-Valerolactam (5.95 g, 60 mmol) in anhydrous THF (15 mL) was added to astirred solution of lithium diisopropylamide (30 mL of a 2M solution inTHF/heptane/ethylbenzene, 60 mmol) in THF (40 mL) at -78° C. under inertatmosphere. After 10 minutes, chlorotrimethylsilane (7.6 mL, 60 mmol)was added and the reaction mixture was allowed to warm to 25° C. for 2h. The reaction mixture was again cooled to -78° C. and a furtherequivalent of lithium diisopropylamide (30 mL of a 2M solution inTHF/heptane/ethylbenzene, 60 mmol) was added. A solution of ethyl5-bromo-3-pyridinecarboxylate (9.2 g, 40 mmol) in anhydous THF (15 mL)was added at -78° C. and the mixture was stirred at 25° C. for 18 h.

The reaction was quenched with methanol (50 mL) and the solvents removedin vacuo. Concentrated HCl (30 mL) and water (10 mL) were carefullyadded and the mixture was heated under reflux for 2 h. Analysis by thinlayer chromatography and GC/MS indicated the presence of product and thecooled (0° C.) mixture was basified with solid sodium hydroxide pellets.The aqueous mixture was extracted with chloroform (3×100 mL), thecombined organic extracts washed with brine (50 mL), dried (Na₂ SO₄) andconcentrated in vacuo. The residue was chromatographed using "flash"silica gel with ethyl acetate as eluant to afford a product which becamedark and gummy on standing. This was therefore used in the next stepwithout further purification. LRMS (EI) m/e 240 (C₁₀ H₁₁ N₂ ⁸¹ Br), 239(C₁₀ H₁₁ N₂ ⁷⁹ Br--⁺ H), 238 (C₁₀ H₁₁ N₂ ⁷⁹ Br), 237 (C₁₀ H₁₁ N₂ ⁷⁹Br--⁺ H).

EXAMPLE 6 5-Bromo-3-(2-piperidinyl)pyridine

5-Bromo-3-(2-piperidein-1-yl)pyridine was dissolved in a mixture ofmethanol (50 mL) and acetic acid (12 mL) and cooled to -40° C. Sodiumborohydride (3.2 g, 85 mmol) was added in portions keeping the internaltemperature below -20° C. The reaction mixture was then stirred at 25°C. for 1 h before the addition of 1M HCl (10 mL) and evaporation of thesolvents in vacuo. Water (100 mL) was added and the resulting solutionmade basic with solid NaOH. The aqueous mixture was extracted withdichloromethane (3×100 mL), the combined organic extracts washed withbrine (50 mL), dried (Na₂ SO₄) and concentrated in vacuo. The residuewas chromatographed using "flash" silica gel with ethyl acetate followedby 10% methanol in ethyl acetate as eluants to afford the title compoundas colorless needles, 2.76 g, 41%. M.p. 97°-97.5° C. (EtOAc); ¹ H NMR(CDCl₃, 300 MHz): δ 8.54 (d, J=2 Hz, 1H), 8.48 (d, J=2 Hz, 1H), 7.91 (t,J=2 Hz, 1H), 3.62 (dd, J=10, 2.5 Hz, 1H), 3.19 (dm, J=12 Hz, 1H), 2.78(ddd, J=12, 12, 3 Hz 1H), 1.4-2.0 (m, 7 H).

EXAMPLE 7 5-Bromo-3-(2-N-tert-butoxycarbonylpiperidinyl)pyridine

5-Bromo-3-(2-piperidinyl)pyridine (3.01 g, 12.5 mmol), di-tert-butyldicarbonate (2.84 g, 13 mmol) and triethylamine (1.81 mL, 13 mmol) weredissolved in dichloromethane (50 mL) and stirred at 0° C. under a dryingtube. 4-Dimethylaminopyridine (80 mg, 0.65 mmol) was added and themixture was stirred at 25° C. for 18 h. The solvents were removed invacuo and the residue chromatographed on "flash" silica gel with ethylacetate:hexane (1:3) as eluant to afford the title compound as a solid,3.7 g, 87%. ¹ H NMR (CDCl₃, 300 MHz): δ 8.51 (s, 1H), 8,38 (s, 1H), 7.62(m, 1H), 5.40 (bs, 1H), 4.03 (d, J=13 Hz, 1H), 2.68 (app. t, J=13 Hz,1H), 2.20 (d, J=14 Hz, 1H), 1.89 (m, 1H), 1.43 (d, 9H), 1.2-1.7 (m, 4H).

EXAMPLE 8 5-(4-Chlorophenyl)-3-(1-methyl-2-pyrrolidinyl)pyridinefumarate

To a stirred solution of 4-bromochlorobenzene (1.91 g, 10 mmol) inanhydrous diethyl ether (10 mL) at -78° C. under inert atmosphere wasslowly added t-butyllithium (11.76 mL of a 1.7M solution in pentane, 20mmol). This was stirred at -78° C. for 30 minutes and zinc chloride (10mL of a 1M solution in diethyl ether, 10 mmol) was added. The reactionmixture was allowed to warm to 25° C. over 30 minutes before beingcannulated into a stirred solution of5-bromo-3-(1-methyl-2-pyrrolidinyl) pyridine (1 g, 4.16 mmol) andbis(triphenylphosphine)palladium (II) chloride (175 mg, 0.25 mmol) inanhydrous THF (10 mL) at 25° C. under inert atmosphere. The reactionmixture was stirred for 18 h before being poured into a saturatedsolution of potassium sodium tartrate (50 mL).

The solids were removed by filtration, the organic phase separated andthe aqueous phase washed with ethyl acetate (2×100 mL). The combinedorganic layers were washed with brine (50 mL), dried (MgSO₄) and thesolvents removed in vacuo. The resulting oil was dissolved in methanol(50 mL) and filtered through paper to remove residual solid catalyst.The filtrate was concentrated under reduced pressure before purificationusing "flash" silica gel column chromatography with ethyl acetate:hexane(1:4, 1:3, 1:1) as eluant to afford5-(4-chlorophenyl)-3-(1-methyl-2-pyrrolidinyl) pyridine, 1.01 g, 91% asan oil.

The above-referenced pyridine was converted into invention compound ofFormula I by the addition of one equivalent of fumaric acid to amethanol (15 mL) solution of the free amine at 25° C. After 30 minutesthe solvent was removed in vacuo and the residue pumped under highvacuum. Trituration with diethyl ether followed by recrystallizationfrom ethyl acetate afforded5-(4-chlorophenyl)-3-(1-methyl-2-pyrrolidinyl)pyridine fumarate, (72%)as a colorless solid. M.p. 159°-160° C. (EtOAc); ¹ H NMR (DMSO-d₆, 300MHz): δ 8.84 (d, J=3 Hz, 1H), 8.58 (d, J=3 Hz, 1H), 8.08 (t, J=2 Hz,1H), 7.79 (d, J=8 Hz, 2H), 7.56 (d, J=8 Hz, 2H), 6.62 (s, 2H), 3.49 (t,J=6 Hz, 1H), 3.32 (m, 1H), 2.52 (m, 1H), 2.28 (m, 1H), 2.24 (s, 3H), 1.9(m, 3H).

EXAMPLE 9 Synthesis of Additional Compounds of Formula I

Repeating the procedure of Example 8, but using the appropriate startingmaterials in place of 4-bromochlorobenzene, the following compounds wereobtained:

(a) 5-(4-Chloro-3-fluorophenyl)-3-(1-methyl-2-pyrrolidinyl)pyridinefumarate;

M.P. 183°-184° C. (EtOAc); ¹ H NMR (DMSO-d₆, 300 MHz): δ 8.89 (s, 1H),8.61 (s, 1H), 8.15 (s, 1H), 7.90 (d, J=12 Hz, 1H), 7.70 (m, 2H), 6.61(s, 2H), 3.55 (m, 1H), 3.37 (m, 1H), 2.53 (m, 1H), 2.26 (s, 3H), 1.90(m, 4 H).

b) 5-(3-Fluorophenyl)-3-(1-methyl-2-pyrrolidinyl)pyridine fumarate;

M.P. 153°-185° C. (EtOAc); ¹ H NMR (DMSO-d₆, 300 MHz): δ 8.86 (d, J=3Hz, 1H), 8.58 (d, J=2 Hz, 1H), 8.10 (t, J=3 Hz, 1H), 7.60 (m, 3H), 7.28(m, 1H), 6.63 (s, 3H), 3.47 (t, J=6 Hz, 1H), 3.32 (m, 1H), 2.49 (m, 1H),2.28 (m, 1H), 2.23 (s, 3H), 1.10 (m, 3H).

c) (E)-5-(2-Phenyl-1-ethenyl)-3-(1-methyl-2-pyrrolidinyl)pyridinefumarate;

M.P. 162°-163° C. (EtOH-EtOAc); ¹ H NMR (DMSO-d₆, 300 MHz): δ 8.68 (d,J=2 Hz, 1H), 8.42 (d, J=2 Hz, 1H), 8.02 (app. t, J=2 Hz, 1H), 7.64 (d,J=7 Hz, 2H), 7.42 (d, J=16.5 Hz, 1H), 7.40 (t, J=7.5 Hz, 2H), 7.30 (d,J=16.5 Hz, 1H), 7.30 (t, J=7 Hz, 1H), 6.62 (s, 3H), 3.28 (m, 2H), 2.39(q, J=9 Hz, 1H), 2.24 (m, 1H), 2.17 (s, 3H), 1.7-1.9 (m, 3H).

d) 5-(3-Chlorophenyl)-3-(1-methyl-2-pyrrolidinyl)pyridine fumarate;

M.P. 139°-141° C. (EtOH); ¹ H NMR (CD₃ OD, 300 MHz): δ 8.78 (d, J=2 Hz,1H), 8.57 (d, J=2 Hz, 1H), 8.21 (t, J=2 Hz, 1H), 7.66 (m, 1H), 7.56 (m,1H), 7.38 (m, 2H), 6.60 (s, 2H), 4.12 (t, J=6 Hz, 1H), 3.66 (m, 1H), 3.0(m, 1H), 2.58 (s, 3H), 2.20 (m, 4H).

e) 5-(3-Fluoro-4-methoxyphenyl)-3-(1-methyl-2-pyrrolidinyl)pyridinefumarate;

M.P. 162°-164° C. (EtOH); ¹ H NMR (CD₃ OD, 300 MHz): δ 8.87 (d, J=3 Hz,1H), 8.62 (d, J=3 Hz, 1H), 8.34 (t, J=3 Hz, 1H), 7.50 (m, 2H), 7.21 (m,1H), 6.70 (s, 4 H), 4.44 (dd, J=10, 7.5 Hz, 1H), 3.90 (s, 3H), 3.90 (m,1H), 3.26 (m, 1H), 2.76 (s, 3H), 2.2-2.7 (m, 4 H).

f) 5-Phenyl-3-(1-methyl-2-pyrrolidinyl)pyridine fumarate;

M.P. 145°-146° C. (EtOAc); ¹ H NMR (D₂ O, 300 MHz): δ 8.55 (s, 1H), 8.33(s, 1H), 8.03 (s, 1H), 7.32 (m, 2H), 7.17 (m, 3H), 6.28 (s, 3H), 4.21(bm, 1H), 3.53 (bm, 1H), 3.03 (bm, 1H), 2.46 (s, 3H), 2.28 (m, 1H),1.9-2.15 (m, 3H).

EXAMPLE 10 5-(4-Fluorophenyl)-3-(1-methyl-2-pyrrolidinyl)pyridinefumarate

To a stirred solution of 4-bromofluorobenzene (1.75 g, 10 mmol) inanhydrous diethyl ether (5 mL) at -10° C. under inert atmosphere wasslowly added n-butyllithium (6.25 mL of a 1.6M solution in hexanes, 10mmol). This was stirred at -10° C. for 30 minutes and zinc chloride (10mL of a 1M solution in diethyl ether, 10 mmol) was added. The mixturewas allowed to warm to 25° C. over 30 minutes before being cannulatedinto a stirred solution of 5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine(1.1 g, 4.6 mmol) and bis(triphenylphosphine)palladium(II) chloride (175mg, 0.25 mmol) in anhydrous THF (10 mL) at 25° C. under inertatmosphere. The reaction mixture was stirred for 18 h before beingpoured into a saturated solution of potassium sodium tartrate (50 mL).

The organic phase was separated and the aqueous phase washed with ethylacetate (2×100 mL). The combined organic layers were washed with brine(50 mL), dried (Na₂ SO₄) and the solvents removed in vacuo. Theresulting oil was dissolved in methanol (50 mL) and filtered throughpaper to remove residual solid catalyst. The filtrate was concentratedunder reduced pressure before purification using "flash" silica gelcolumn chromatography with ethyl acetate:hexane (1:4, 1:3, 1:1) aseluant to afford 5-(4-fluorophenyl)-3-(1-methyl-2-pyrrolidinyl)pyridine,793 mg, 63% as an oil.

The pyridine derivative described above was converted to a compound ofthe invention having Formula I by the addition of one equivalent offumaric acid to a methanol (15 mL) solution of the free amine at 25° C.After 30 minutes the solvent was removed in vacuo and the residue pumpedunder high vacuum. Trituration with diethyl ether followed byrecrystallization from ethyl acetate afforded5-(4-fluorophenyl)-3-(1-methyl-2-pyrrolidinyl)pyridine fumarate, (63%).M.p. 159°-160° C. (EtOAc); ¹ H NMR (D₂ O, 300 MHz): δ 8.87 (s, 1H), 8.68(s, 1H), 8.26 (s, 1H), 7.73 (dd, J=8, 6 Hz, 2H), 7.30 (app. t, J=8 Hz,2H), 6.61 (s, 2H), 4.56 (bm, 1H), 3.91 (bm, 1H), 3.41 (bm, 1H), 2.83 (s,3H), 2.67 (m, 1H), 2.3-2.5 (m, 3H).

EXAMPLE 11 Synthesis of Additional Compounds of Formula I

Repeating the procedure of Example 10, but using the appropriatestarting materials in place of 4-bromofluorobenzene, the followingcompounds were obtained:

(a) 5-(4-Methylthiophenyl)-3-(1-methyl-2-pyrrolidinyl)pyridine fumarate;

M.P. 133°-134° C. (EtOAc); ¹ H NMR (DMSO-d₆, 300 MHz): δ 8.81 (d, J=2Hz, 1H), 8.52 (d, J=2 Hz, 1H), 8.26 (app. t, J=2 Hz, 1H), 7.70 (d, J=8Hz, 2H), 7.38 (d, J=8 Hz, 2H), 6.61 (s, 2H), 3.42 (t, J=8 Hz, 1H), 3.30(app. t, J=8.5 Hz, 1H), 2.53 (s, 3H), 2.44 (q, J=8 Hz, 1H), 2.26 (m,1H), 2.21 (s, 3H), 1.7-2.0 (m, 3H).

(b) 5-(3-Methylphenyl)-3-(1-methyl-2-pyrrolidinyl)pyridine fumarate;

M.P. 144.5°-145.5° C. (EtOAc); ¹ H NMR (DMSO-d₆, 300 MHz): δ 8.78 (d,J=2 Hz, 1H), 8.52 (d, J=2 Hz, 1H), 8.00 (t, J=2 Hz, 1H), 7.55 (bs, 1H),7.52 (d, J=8 Hz, 1H), 7.39 (t, J=8 Hz, 1H), 7.25 (d, J=7.5 Hz, 1H), 6.62(s, 3H), 3.37 (t, J=8 Hz, 1H), 3.27 (app. t, J=8 Hz, 1H), 2.40 (q, J=8.5Hz, 1H), 2.39 (s, 3H), 2.26 (m, 1H), 2.19 (s, 3H), 1.7-2.0 (m, 3H).

(c) 5-(3-Trifluoromethylphenyl)-3-(1-methyl -2-pyrrolidinyl)pyridinefumarate;

M.P. 157.5°-158.5° C. (EtOH); ¹ H NMR (DMSO-d₆, 300 MHz): δ 8.86 (d,J=2.5 Hz, 1H), 8.60 (d, J=2 Hz, 1H), 8.10 (m, 3H), 7.78 (m, 2H), 6.62(s, 4 H), 3.43 (t, J=8 Hz, 1H), 3.27 (dt, J=8, 2 Hz, 1H), 2.41 (q, J=9Hz, 1H), 2.25 (m, 1H), 2.20 (s, 3H), 1.8-2.0 (m, 3H).

(d) 5-(2-Methylphenyl)-3-(1-methyl-2-pyrrolidinyl)pyridine fumarate;

M.P. 141°-142° C. (EtOH-EtOAc); ¹ H NMR (DMSO-d₆, 300 MHz): δ 8.56 (d,J=2 Hz, 1H), 8.50 (d, J=2 Hz, 1H), 7.79 (t, J=2 Hz, 1H), 7.29 (m, 4 H),6.61 (s, 3H), 3.51 (app. t, J=8 Hz, 1H), 3.32 (d t, J=8, 2 Hz, 1H), 2.49(q, J=8.5 Hz, 1H), 2.28 (m, 1H), 2.26 (s, 3H), 2.25 (s, 3H), 1.8-1.9 (m,3H).

(e) 5-(2-Methoxyphenyl)-3-(1-methyl-2-pyrrolidinyl)pyridine fumarate;

M.P. 132°-133° C. (EtOAc); ¹ H NMR (DMSO-d₆, 300 MHz): δ 8.60 (d, J=2Hz, 1H), 8.48 (d, J=2 Hz, 1H), 7.85 (t, J=2 Hz, 1H), 7.38 (m, 2H), 7.16(d, J=8 Hz, 1H), 7.07 (t, J=7.5 Hz, 1H), 6.61 (s, 3H), 3.79 (s, 3H),3.38 (t, J=8 Hz, 1H), 3.27 (app. t, J=8.5 Hz, 1H), 2.42 (q, J=9 Hz, 1H),2.25 (m, 1H), 2.21 (s, 3H), 1.7-1.9 (m, 3H).

(f) 5-(4-Methoxyphenyl)-3-(1-methyl-2-pyrrolidinyl)pyridine fumarate;

M.P. 97°-98° C. (EtOH); ¹ H NMR (CD₃ OD, 300 MHz): δ 8.67 (d, J=2 Hz,1H), 8.40 (d, J=2 Hz, 1H), 8.14 (t, J=3 Hz, 1H), 7.45 (bd, J=9 Hz, 2H),6.86 (bd, J=9 Hz, 2H), 6.51 (s, 4 H), 4.25 (q, J=6 Hz, 1H), 3.70 (m,1H), 3.64 (s, 3H), 3.12 (m, 1H), 2.58 (s, 3H), 2.0-2.4 (m, 4 H).

(g) 5-(4-Phenoxyphenyl)-3-(1-methyl-2-pyrrolidinyl)pyridine fumarate;

M.P. 126°-128° C. (EtOAc); ¹ H NMR (CD₃ OD, 300 MHz): δ 8.79 (d, J=2 Hz,1H), 8.54 (d, J=3 Hz, 1H), 8.26 (t, J=3 Hz, 1H), 7.61 (bd, J=9 Hz, 2H),7.28 (app. t, J=9 Hz, 2H), 6.9-7.1 (m, 5 H), 6.60 (s, 4 H), 4.34 (dd,J=12, 9 Hz, 1H), 3.79 (m, 1H), 3.20 (m, 1H), 2.51 (s, 3H), 2.3-2.5 (m,2H), 2.1-2.3 (m, 2H).

(h) 5-(3,4-Methylenedioxyphenyl)-3-(1-methyl-2-pyrrolidinyl)pyridinefumarate;

M.P. 168°-170° C. (EtOH); ¹ H NMR (CD₃ OD, 300 MHz): δ 8.71 (s, 1H),8.47 (s, 1H), 8.15 (s, 1H), 7.08 (m, 2H), 6.82 (m, 1H), 6.58 (s, 3H),5.90 (s, 2H), 4.30 (app. t, J=7 Hz, 1H), 3.75 (m, 1H), 3.14 (m, 1H),2.63 (s, 3H), 2.1-2.5 (m, 4H).

(i) 5-(3,4-Difluorophenyl)-3-(1-methyl-2-pyrrolidinyl)pyridine fumarate;

M.P. 158°-160° C. (EtOH); ¹ H NMR (CD₃ OD, 300 MHz): δ 8.61 (d, J=2 Hz,1H), 8.42 (d, J=2 Hz, 1H), 8.12 (t, J=2 Hz, 1H), 7.40 (m, 1H), 7.28 (m,1H), 7.10 (m, 1H), 6.60 (s, 2H), 4.13 (app. t, J=7 Hz, 1H), 3.64 (m,1H), 2.99 (m, 1H), 2.49 (s, 3H), 2.25 (m, 2H), 2.03 (m, 2H).

(j) 5-(2-Trifluoromethylphenyl)-3-(1-methyl-2-pyrrolidinyl)pyridinefumarate;

M.P. 141°-143° C. (EtOH); ¹ H NMR (CD₃ OD, 300 MHz): δ 8.81 (d, J=3 Hz,1H), 8.62 (s, 1H), 8.12 (s, 1H), 7.88 (d, J=6 Hz, 1H), 7.76 (t, J=7 Hz,1H), 7.67 (t, J=7 Hz, 1H), 7.50 (d, J=6 Hz, 1H), 6.69 (s, 3H), 4.46 (dd,J=12, 7.5 Hz, 1H), 3.86 (m, 1H), 3.27 (m, 1H), 2.77 (s, 3H), 2.60 (m,1H), 2.2-2.5 (m, 3H).

(k) 5-(4-Trifluoromethylphenyl)-3-(1-methyl -2-pyrrolidinyl)pyridinefumarate;

M.P. 159°-160° C. (EtOH); ¹ H NMR (CD₃ OD, 300 MHz): δ 8.98 (d, J=2 Hz,1H), 8.74 (d, J=2 Hz, 1H), 8.46 (t, J=2 Hz, 1H), 7.93 (d, J=9 Hz, 2H),7.81 (d, J=9 Hz, 2H), 6.67 (s, 3 H), 4.46 (dd, J=10.5, 7.5 Hz, 1H), 3.90(m, 1H), 3.29 (m, 1H), 2.77 (bs, 3H), 2.60 (m, 1H), 2.2-2.7 (m, 4H).

(1) 5-(2-Naphthyl)-3-(1-methyl-2-pyrrolidinyl)pyridine fumarate;

M.P. 142°-145° C. (EtOH); ¹ H NMR (CD₃ OD, 300 MHz): δ 8.95 (d, J=2 Hz,1H), 8.58 (d, J=2 Hz, 1H), 8.35 (t, J=2 Hz, 1H), 8.14 (bs, 1H), 7.7-8.0(m, 4H), 7.45 (m, 2H), 6.62 (s, 3H), 4.24 (dd, J=10, 7.5 Hz, 1H), 3.70(m, 1H), 3.09 (m, 1H), 2.63 (s, 3H), 2.48 0 (m, 1H), 2.1-2.4 (m, 3H).

(m) 5-(4-Biphenyl)-3-(1-methyl-2-pyrrolidinyl)pyridine fumarate;

M.P. 193°-194° C. (EtOH); ¹ H NMR (DMSO-d₆, 300 MHz): δ 8.89 (s, 1H),8.57 (s, 1H), 8.12 (s, 1 H), 7.84 (dd, J=15, 9 Hz, 4 H), 7.74 (d, J=9Hz, 2H), 7.50 (app. t, J=9 Hz, 2H), 7.40 (app. t, J=9 Hz, 1H), 6.63 (s,2H), 3.48 (app. t, J=9, Hz, 1H), 3.34 (app. t, J=9, Hz, 1H), 2.5 (m,1H), 2.30 (m, 1H), 2.25 (s, 3H), 1.75-2.05 (m, 3H).

EXAMPLE 12 5-(4-Methylphenyl)-3-(1-methyl-2-pyrrolidinyl)pyridinefumarate

5-Bromo-3-(1-methyl-2-pyrrolidinyl)pyridine (1.2 g, 5 mmol) andbis(triphenylphosphine)palladium(II) chloride (175 mg, 0.25 mmol) werestirred in anhydrous THF (10 mL) at 25° C. under inert atmosphere.p-Tolylmagnesium bromide (10 mL of a 1M solution in diethyl ether, 10mmol) was added and the reaction mixture was stirred at 25° C. for 18 h.

The reaction mixture was filtered through celite, methanol (10 mL) wasadded and the solvents removed in vacuo. Concentrated HCl (10 mL) inwater (50 mL) was added to the residue and this was washed with hexane(2×30 mL). The aqueous phase was carefully basified (Na₂ CO₃) andextracted with ethyl acetate (3×30 mL). The combined organic extractswere washed with water (10 mL), brine (10 mL), dried (Na₂ SO₄) andconcentrated.

The resulting oil was dissolved in methanol (50 mL) and filtered throughpaper to remove residual solid catalyst. The filtrate was concentratedunder reduced pressure before purification using "flash" silica gelcolumn chromatography with ethyl acetate:hexane (1:3, 1:2) as eluant toafford 5-(4-methylphenyl)-3-(1-methyl-2-pyrrolidinyl)pyridine, 740 mg,59% as an oil. This was converted to the title compound by the additionof one equivalent of fumaric acid to a methanol (15 mL) solution of thefree amine at 25° C. After 30 minutes the solvent was removed in vacuoand the residue pumped under high vacuum. Trituration with diethyl etherfollowed by recrystallization from ethyl acetate afforded5-(4-methylphenyl)-3-(1-methyl-2-pyrrolidinyl)pyridine fumarate, (20%).A second crop of crystalline product was obtained from the motherliquors by recrystallization (40%). M.p. 155°-157° C. (EtOAc); ¹ H NMR(D₂ O, 300 MHz): δ 8.79 (d, J=2 Hz, 1H), 8.56 (d, J=2 Hz, 1H), 8.18 (s,1H), 7.53 (d, J=8 Hz, 2H), 7.29 (d, J=8 Hz, 2H), 6.54 (s, 2H), 4.45 (bm,1H), 3.81 (bm, 1H), 3.31 (bm, 1H), 2.72 (s, 3H), 2.55 (m, 1H), 2.2-2.4(s, 3H),(m, 6H).

EXAMPLE 13 5-benzyl-3-(1-methyl-2-pyrrolidinly)pyridine furmate

Repeating the procedure of Example 12, but using benzylmagnesiumchloride in place of p-tolylmagnesium bromide,5-benzyl-3-(1-methyl-2-pyrrolidinyl)pyridine fumarate was obtained:

M.P. 151° C. (EtOAc); ¹ H NMR (DMSO-d₆, 300 MHz): δ 8.69 (s, 1H), 8.39(d, J=3 Hz, 1H), 7.33 (m, 2H), 7.21 (m, 4 H), 6.63 (s, 3H), 4.10 (s,2H), 3.60 (t, J=7 Hz, 1H), 3.27 (m, 1H), 2.35 (q, J=8 Hz, 1H), 2.10 (s,3H), 2.05 (m, 1H), 1.80 (m, 3H), 1.55 (m, 1H).

EXAMPLE 14 5-(2-Furanyl)-3-(1-methyl-2-pyrrolidinyl)pyridine fumarate

To a stirred solution of furan (0.73 mL, 10 mmol) in anhydrous diethylether (10 mL) at -78° C. under inert atmosphere was slowly addedt-butyllithium (5.9 mL of a 1.7M solution in pentane, 10 mmol). This wasstirred at -78° C. for 2 h and zinc chloride (10 mL of a 1M solution indiethyl ether, 10 mmol) was added. The reaction mixture was stirred at-78° C. for 1.5 h and then allowed to warm to 25° C. before cannulationinto a stirred solution of 5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine(964 mg, 4 mmol) and bis(triphenylphosphine)palladium(II) chloride (175mg, 0.25 mmol) in anhydrous THF (20 mL) at 25° C. under inertatmosphere. The reaction mixture was stirred for 18 h before beingpoured into a saturated solution of potassium sodium tartrate (100 mL)and ethyl acetate (50 mL) was added.

The organic phase was separated and the aqueous phase washed with ethylacetate (3×50 mL). The combined organic layers were washed with brine(40 mL), dried (Na₂ SO₄) and the solvents removed in vacuo. Theresulting oil was dissolved in methanol (50 mL) and filtered throughpaper to remove residual solid catalyst. The filtrate was concentratedunder reduced pressure before purification using "flash" silica gelcolumn chromatography with ethyl acetate:hexane (1:4, 1:2) as eluant toafford 5-(furanyl)-3-(1-methyl-2-pyrrolidinyl)pyridine, 734 mg, 80%.

The above-described pyridine derivative was converted to inventioncompound of Formula I by the addition of one equivalent of fumaric acidto a methanol (15 mL) solution of the free amine at 25° C. After 30minutes the solvent was removed in vacuo and the residue pumped underhigh vacuum. Trituration with diethyl ether followed byrecrystallization from ethyl acetate afforded5-(2-furanyl)-3-(1-methyl-2-pyrrolidinyl)pyridine fumarate, (43%). M.p.147°-148° C. (EtOAc); ¹ H NMR (DMSO-d₆, 300 MHz): δ 8.71 (s, 1H), 8.29(s, 1H), 7.93 (bs, 1H), 7.64(s, 1H), 6.95 (d, J=3 Hz, 1H), 6.46 (bm,1H), 6.42 (s, 3H), 3.40 (m, 1H), 3.20 (m, 1H), 2.39 (m, 1H), 2.08 (m, 4H), 1.74 (m, 3H).

EXAMPLE 15 5-(Trimethylsilyl)-3-(1-methyl-2-pyrrolidinyl)pyridinefumarate

To a stirred solution of 5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine(1.2 g, 5 mmol) in anhydrous diethylether (20 mL) at -78° C. under inertatmosphere was slowly added n-butyllithium (3.2 mL of a 1.6M solution inhexanes, 5 mmol). This was stirred at -78° C. for 30 minutes andchlorotrimethylsilane (0.63 mL, 5 mmol) was added. The reaction mixturewas allowed to warm to 25° C. and stirred for 2 h under inertatmosphere. The reaction was quenched with a mixture of saturated NaHCO₃solution (10 mL) and water (10 mL) and ethyl acetate (10 mL) was added.

The organic phase was separated and the aqueous phase washed with ethylacetate (3×20 mL). The combined organic extracts were washed with brine(20 mL), dried (Na₂ SO₄) and the solvents removed in vacuo. Purificationwas accomplished using "flash" silica gel column chromatography twicewith ethyl acetate:hexane (1:3, 1:2) as eluant to afford5-(trimethylsilyl)-3-(1-methyl-2-pyrrolidinyl) pyridine, 385 mg, 33% asan oil.

The above-described pyridine derivative was converted into inventioncompound of Formula I by the addition of one equivalent of fumaric acidto a methanol (5 mL) solution of the free amine at 25° C. After 30minutes the solvent was removed in vacuo and the residue pumped underhigh vacuum. Trituration with diethyl ether followed byrecrystallization from ethyl acetate afforded5-trimethylsilyl-3-(1-methyl-2-pyrrolidinyl)pyridine fumarate, (51%).M.p. 161°-162° C. (EtOAc); ¹ H NMR (D₂ O, 300 MHz): δ 8.48 (s, 2H), 8.26(s, 1H), 6.25 (s, 3H), 4.24 (bm, 1H), 3.53 (bm, 1H), 3.03 (bm, 1H), 2.43(s, 3H), 2.27 (m, 1H), 1.9-2.1 (m, 3H), 0.0 (s, 9H).

EXAMPLE 16 5-Phenylethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine fumarate

Phenylacetylene (2.2 mL, 20 mmol) was added to a stirred solution of5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine (2.17 g, 9 mmol),bis(triphenylphosphine)palladium(II) chloride (700 mg, 1 mmol),copper(I)iodide (380 mg, 2 mmol) and triethylamine (5.6 mL, 40 mmol) inanhydrous THF (20 mL) at 25° C. under inert atmosphere. The reactionmixture was stirred for 6 days before ethyl acetate (50 mL) was addedand the mixture poured into water (50 mL).

The organic phase was separated and the aqueous layer extracted withisopropyl acetate (3×50 mL). The combined organic extracts were washedwith brine (50 mL), dried (MgSO₄) and filtered through celite before thesolvents were removed in vacuo. The dark residue was extracted severaltimes with methanol and the combined extracts concentrated in vacuo. Theresulting oil was purified using "flash" silica gel columnchromatography with ethyl acetate:hexane (1:9, 1:4) as eluant to afford5-phenylethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine, 1.22 g, 52%.

The above-described pyridine derivative was converted into inventioncompound of Formula I by the addition of one equivalent of fumaric acidto a methanol (10 mL) solution of the free amine at 25° C. After 30minutes the solvent was removed in vacuo and the residue pumped underhigh vacuum. Trituration with diethyl ether followed byrecrystallization from isopropyl acetate afforded5-(phenylethynyl)-3-(1-methyl-2-pyrrolidinyl)pyridine fumarate, (56%).M.p. 152°-154° C. (decomp., iPrOAc); ¹ H NMR (DMSO-d₆, 300 MHz): δ9.6-10.4 (bs, 1H), 8.5-8.9 (bs, 1H), 8.00 (s, 1H), 7.60(m, 2H), 7.46 (m,3H), 6.63 (s, 3H), 3.51 (app. t, J=8 Hz, 1H), 3.33 (app. t, J=8 Hz, 1H),2.51 (m, 1H), 2.24 (s, 3H), 2.19-2.32 (m, 1H), 1.7-2.0 (m, 3H).

EXAMPLE 17 5-Ethynyl-methyl-2-pyrrolidinyl)pyridine fumarate

Repeating the procedure of Example 16, but using trimethylsilylacetylenein place of phenylacetylene,-ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine and the fumarate derivativethereof were obtained as follows.-Trimethylsilylethynyl-3-(1-methyl-2-pyrrolidinyl) pyridine (516 mg, 2mmol) and cesium carbonate (200 mg, 0.6 mmol) were dissolved in methanol(10 mL) and heated under reflux for 5 h. After cooling the solvents wereremoved in vacuo and the residue dissolved in ethyl acetate (40 mL) andwashed with water (10 mL). The aqueous layer was extracted with ethylacetate (40mL) and the combined organic extracts washed with brine (10mL), dried (Na₂ SO₄) and concentrated in vacuo. The crude product waschromatographed on "flash" silica gel with ethyl acetate:hexane (1:9,1:4, 1,3) to afford 5-ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine as anoil, 218 mg, 59%.

¹ H NMR (CDCl₃, 300 MHz): δ 8.58 (d, J=2 Hz, 1H), 8.48 (d, J=2 Hz, 1H),7.80 (app. t, J=2 Hz, 1H), 3.23 (t, J=8 Hz, 1H), 3.18 (s, 1H), 3.08(app. t, J=8.5 Hz, 1H), 2.30 (dd, J=18, 9 Hz, 1H), 2.21 (m, 1H), 2.16(s, 3H), 1.65-2.00 (m, 3H).

5-Ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine fumarate

M.P. 148°-149° C. (EtOH/EtOAc); ¹ H NMR (DMSO-d₆, 300 MHz): δ 8.57 (d,J=2 Hz, 1H), 8.54 (d, J=2 Hz, 1H), 7.83 (app. t, J=2 Hz, 1H), 6.61 (s,2H), 4.44 (s, 1H), 3.25 (app. dd, J=16, 8 Hz, 1H), 3.19 (dd, J=8, 3 Hz,1H), 2.33 (app. dd, J=16, 8 Hz, 1H), 2.20 (m, 1H), 2.12 (s, 3H), 1.6-1.9(m, 3H).

EXAMPLE 18 4-Bromophenyl-tert-butyldimethylsilyl ether

4-Bromophenol (5.76 g, 30 mmol), imidazole (4.08 g, 60 mmol) andtert-butyldimethylsilyl chloride (5.02 g, 33 mmol) were stirred inanhydrous DMF (100 mL) at 25° C. for 18 h. The reaction mixture was thenpoured into water (100 mL) and extracted with ethyl acetate (2×75 mL).The combined extracts were washed with water (2×75 mL), brine (75 mL)and dried (MgSO₄) before concentration in vacuo. The crude product waspurified using "flash" silica gel column chromatography with ethylacetate:hexane (1:4) as eluant to afford the title compound as an oil,7.9 g, 92%. ¹ H NMR (CDCl₃, 300 MHz): δ 7.33 (app. dt, J=9, 3, 1 Hz,2H), 6.73 (app. dt, J=9, 3, 1 Hz, 2H) 0.98 (s, 9H), 0.21 (s, 6 H).

EXAMPLE 19 4-Bromo-3-halophenyl-tert-butyldimethylsilyl ethers

Repeating the procedure of Example 18, but using the appropriatestarting materials in place of 4-bromophenol, the following compoundswere obtained:

(a) 4-Bromo-3-chlorophenyl-tert-butyldimethylsilyl ether

¹ H NMR (CDCl₃, 300 MHz): δ 7.47 (d, J=2 Hz, 1H), 7.24 (dd, J=9, 2 Hz,1H), 6.75 (d, J=9 Hz, 1H), 1.02 (s, 9H),0.22 (s, 6 H).

(b) 4-Bromo-3-fluorophenyl-tert-butyldimethylsilyl ether

¹ H NMR (CDCl₃, 300 MHz): δ 7.61 (m, 1H), 7.31 (m, 1H), 6.91 (m, 1H),1.01 (s, 9H), 0.23 (s, 6H).

EXAMPLE 20 5-(4-Hydroxyphenyl)-3-(1-methyl-2-pyrrolidinyl)pyridinefumarate

To a stirred solution of 4-bromophenyl-tert-butyldimethylsilyl ether(2.87 g, 10 mmol) in anhydrous diethyl ether (10 mL) at -78° C. underinert atmosphere was slowly added t-butyllithium (11.75 mL of a 1.7Msolution in pentane, 20 mmol). This was stirred at -78° C. for 30minutes and zinc chloride (10 mL of a 1M solution in diethyl ether, 10mmol) was added. The mixture was allowed to warm to 25° C. over 30minutes before being cannulated into a stirred solution of5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine (1 g, 4.16 mmol) andbis(triphenylphosphine)palladium(II) chloride (175 mg, 0.25 mmol) inanhydrous THF (10 mL) at 25° C. under inert atmosphere. The reactionmixture was stirred for 18 h before being poured into a saturatedsolution of potassium sodium tartrate (50 mL).

The solids were removed by filtration, the organic phase separated andthe aqueous phase washed with ethyl acetate (2×100 mL). The combinedorganic layers were washed with brine (50 mL), dried (MgSO₄) and thesolvents removed in vacuo. The resulting oil was dissolved in methanol(50 mL) and filtered through paper to remove residual solid catalyst.The filtrate was concentrated under reduced pressure before purificationusing "flash" silica gel column chromatography with ethyl acetate:hexane(1:4, 1:3, 1:1) as eluant to afford5-(4-tert-butyldimethylsilyloxyphenyl)-3-(1-methyl-2-pyrrolidinyl)pyridine,890 mg, 58% as an oil.

The above-described pyridine derivative (750 mg, 2.04 mmol) wasdissolved in methanol (40 mL) and cesium fluoride (620 mg, 4.08 mmol)was added. The stirred mixture was heated at reflux for 18 h under inertatmosphere. After cooling the solvent was removed in vacuo and theresulting oil was dissolved in ethyl acetate (50 mL). This was washedwith water (20 mL), brine (20 mL), dried (MgSO₄) and concentrated. Thecrude material was chromatographed on "flash" silica gel with ethylacetate:hexane (1:2 ) to 10% methanol:ethyl acetate as eluant to afford5-(4-hydroxyphenyl)-3-(1-methyl-2-pyrrolidinyl)pyridine 480 mg, 93% as acolorless foam, ¹ H NMR (CDCl₃, 300 MHz): δ 8.66 (d, J=2 Hz, 1H), 8.43(d, J=2 Hz, 1H), 7.90 (s, 1H), 7.32 (d, J=9 Hz, 2H), 6.81 (d, J=9 Hz,2H), 3.33 (t, J=8 Hz, 1H), 3.22 (t, J=8 Hz, 1H), 2.41 (m, 1H), 2.28 (s,3H), 2.10 (m, 2H), 1.93 (m, 2H).

The above-described pyridine derivative was converted into inventioncompound of Formula I by the addition of one equivalent of fumaric acidto a methanol (15 mL) solution of the free amine at 25° C. After 30minutes the solvent was removed in vacuo and the residue pumped underhigh vacuum. Trituration with diethyl ether followed byrecrystallization from ethyl acetate afforded5-(4-hydroxyphenyl)-3-(1-methyl-2-pyrrolidinyl)pyridine fumarate, (46%).M.p. 136°-137° C. (EtOAc); ¹ H NMR (DMSO-d₆, 300 MHz): δ 8.76 (s, 1H),8.47 (s, 1H), 8.00 (s, 1H), 7.58 (d, J=6 Hz, 2H), 6.90 (d, J=6 Hz, 2H),6.62 (s, 2H), 3.53 (m, 1H), 3.37 (m, 1H), 2.55 (m, 1H), 2.30 (s, 3H),1.9 (m, 4H).

EXAMPLE 215-(4-Hydroxy-3-halophenyl)-3-(1-methyl-2-pyrrolidinyl)pyridine fumarates

Repeating the procedure of Example 20, but using the appropriatestarting materials in place of 4-bromophenyl-tert-butyldimethylsilylether, the following compounds were obtained:

(a) 5-(4-Hydroxy-3-chlorophenyl)-3-(1-methyl -2-pyrrolidinyl)pyridine

¹ H NMR (CDCl₃, 300 MHz): δ 8.62 (d, J=2 Hz, 1H), 8.41 (d, J=2 Hz, 1H),7.92 (t, J=2 Hz, 1H), 7.60 (d, J=3 Hz, 1H), 7.37 (dd, J=9, 3 Hz, 1H),7.03 (d, J=9 Hz, 1H) 4.10 (s, 1H), 3.29 (t, J=8 Hz, 1H), 3.20 (t, J=8Hz, 1H), 2.35 (m, 1H), 2.23 (s, 3H), 2.03 (m, 1H), 1.87 (m, 3H);

5-(4-hydroxy-3-chlorophenyl)-3-(1-methyl-2-pyrrolidinyl)pyridinefumarate

M.P. 199°-201° C. (decomp., EtOAc); ¹ H NMR (DMSO-d₆, 300 MHz): δ 8.81(d, J=2 Hz, 1H), 8.52 (s, 1 H), 8.08 (s, 1H), 7.77 (d, J=2 Hz, 1H), 7.57(dd, J=5, 2 Hz, 1H), 7.12 (d, J=8 Hz, 1H), 6.62 (s, 2H), 3.65 (t, J=7Hz, 1H), 3.42 (t, J=5 Hz, 1H), 2.59 (m, 1H), 2.30 (s, 3H), 1.95 (m, 4H).

(b) 5-(4-Hydroxy-3-fluorophenyl)-3-(1-methyl-2-pyrrolidinyl)pyridine,

¹ H NMR (CDCl₃, 300 MHz): δ 8.65 (d, J=2 Hz, 1H), 8.44 (d, J=2 Hz, 1H),7.81 (t, J=2 Hz, 1H), 7.16 (m, 1H), 7.10 (m, 1H), 6.90 (t, J=9 Hz, 1H),3.36 (t, J=9 Hz, 1H), 3.22 (t, J=9 Hz, 1H), 2.40 (dd, J=12, 6 Hz, 1H),2.31 (m, 1H), 2.26 (s, 3H), 2.11 (m, 1H), 1.93 (m, 2H);

5-(4-hydroxy-3-fluorophenyl)-3-(1-methyl-2-pyrrolidinyl)pyridinefumarate

M.P. 192°-193° C. (EtOH); ¹ H NMR (CD₃ OD, 300 MHz): δ 8.66 (d, J=3 Hz,1H), 8.42 (d, J=3 Hz, 1H), 8.13 (t, J=3 Hz, 1H), 7.32 (m, 1H), 7.19 (m,1H), 6.86 (t, J=9 Hz, 1H), 6.49 (s, 2H), 4.18 (t, J=10, 9 Hz, 1H), 3.67(m, 1H), 3.03 (m, 1H), 2.55 (s, 3H), 2.05-2.45 (m, 4H).

EXAMPLE 22 5-(4-Fluorophenyl)-3-(2-piperidinyl)pyridine fumarate

To a stirred solution of 4-bromofluorobenzene (1.75 g, 10 mmol) inanhydrous diethyl ether (5 mL) at -10° C. under inert atmosphere wasslowly added n-butyllithium (6.25 mL of a 1.6M solution in hexanes, 10mmol). This was stirred at -10° C. for 30 minutes and zinc chloride (10mL of a 1M solution in diethyl ether, 10 mmol) was added. The mixturewas allowed to warm to 25° C. over 30 minutes before being cannulatedinto a stirred solution of5-bromo-3-(2-N-t-butoxycarbonylpiperidinyl)pyridine (1.53 g, 4.5 mmol)and bis(triphenylphosphine)palladium(II) chloride (175 mg, 0.25 mmol) inanhydrous THF (15 mL) at 0° C. under inert atmosphere. The reactionmixture was then stirred at 25° C. for 18 h before being poured into asaturated solution of potassium sodium tartrate (100 mL) and ethylacetate (50 mL).

The organic phase was separated and the aqueous phase washed with ethylacetate (2×50 mL). The combined organic layers were washed withsaturated sodium carbonate solution (40 mL), brine (50 mL), dried (Na₂SO₄) and the solvents removed in vacuo. The resulting oil was dissolvedin methanol (50 mL) and filtered through paper to remove residual solidcatalyst. The filtrate was concentrated under reduced pressure beforepurification using "flash" silica gel column chromatography with ethylacetate:hexane (1:9, 1:4) as eluant to afford5-(4-fluorophenyl)-3-(2-N-tert-butoxycarbonylpiperidinyl)pyridine, 1.45g, 90% as an oil.

The above-described pyridine derivative (1.25 g, 3.5 mmol) was dissolvedin a mixture of dichloromethane (10 mL) and trifluoroacetic acid (10 mL)and this was stirred at 25° C. for 18 h. The solvents were removed invacuo and the crude material dissolved in ethyl acetate (50 mL).Saturated sodium carbonate solution (30 mL) was added and the organiclayer separated. The aqueous phase was extracted with two furtherportions of ethyl acetate (2×30 mL), the combined organic extractswashed with brine (20 mL), dried (Na₂ SO₄) and concentrated in vacuo.The residue was chromatographed on silica gel with ethyl acetate, thenmethanol:ethyl acetate (1: 9 ) as eluant to afford5-(4-fluorophenyl)-3-(2-piperidinyl)pyridine, 940 mg, 100%. NMR (CDCl₃,300 MHz): δ 8.69 (d, J=2 Hz, 1H), 8.55 (d, J=2 Hz, 1H), 7.93 (t, J=2 Hz,1H), 7.56 (m, 2H), 7.16 (app. tm, J=9 Hz, 2H), 3.18 (d, J=12 Hz, 1H),2.83 (td, J=12, 3 Hz, 1H), 2.61 (bs exch., 1H), 1.92 (m, 2H), 1.45-1.75(m, 6H).

The above described pyridine derivative was converted into inventioncompound of Formula I by the addition of one equivalent of fumaric acidto a methanol (15 mL) solution of the free amine at 25° C. After 30minutes the solvent was removed in vacuo and the residue pumped underhigh vacuum. Trituration with diethyl ether resulted in the formation of5-(4-fluorophenyl)-3-(2-piperidinyl)pyridine fumarate (70%) as acolorless solid. M.p. 209°-210° C. (decomp., Et₂ O); ¹ H NMR (DMSO-d₆,300 MHz): δ 8.86 (s, 1H), 8.63 (s, 1H), 8.32 (s, 1H), 7.81 (dd, J=8, 5Hz, 2H), 7.32 (app. t, J=8 Hz, 2H), 6.49 (s, 2H), 4.24 (dd, J=10, 4 Hz,1H), 3.37 (d, J=12 Hz, 1H), 2.97 (m, 1H), 1.5-2.1 (m, 6H).

EXAMPLE 23 5-3-(1-Hydroxy-2-propynyl)!-3-(1-methyl-2-pyrrolidinyl)pyridine fumarate

A mixture of 5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine (1 g, 4.15mmol), 10% palladium on charcoal (106 mg, 0.1 mmol), copper(I)iodide (38mg, mmol), triphenylphosphine (104 mg, 0.4 mmol) and potassium carbonate(1.38 g, 10 mmol) in DME (10 mL) and water (10 mL) was stirred at 25° C.After 0.5 h, propargyl alcohol (0.58 mL, 10 mmol) was added and thereaction flask was heated at 80° C. for 18 h. The cooled mixture wasthen filtered through celite and the filtrate concentrated in vacuo. Themixture was then acidified with 1M HCl (50 mL) and extracted withtoluene (50 mL). The aqueous layer was made basic with solid potassiumcarbonate and extracted with ethyl acetate (2×100 mL). The combinedethyl acetate extracts were washed with water (50 mL), dried (MgSO₄) andconcentrated to afford an oil (858 mg, 96%). The crude product waspurified by silica gel column chromatography with ethyl acetate:hexane(1:1) to ethyl acetate as eluants to afford5-(2-propyn-1-ol)-3-(1-methyl-2-pyrrolidinyl)pyridine (660 mg, 73%).This was converted to the title compound by the addition of oneequivalent of fumaric acid to a methanol (10 mL) solution of the freeamine at 25° C. After 30 minutes the solvent was removed in vacuo andthe residue pumped under high vacuum. Trituration with diethyl etherfollowed by recrystallization from ethyl acetate afforded 5-3-(1-hydroxy-2-propynyl)!-3-(1-methyl-2-pyrrolidinyl)pyridine fumarate,(96%). M.p. 167°-168° C. (EtOAc); ¹ H NMR (DMSO-d₆, 300 MHz): δ 8.52 (m,2H), 7.80 (app t, J=2 Hz, 1H), 6.61 (s, 2H), 4.43 (s, 2H), 3.31 (app. t,J=8 Hz, 1H), 3.23 (td, J=8, 2 Hz, 1H), 2.37 (dd, J=9, 7.5 Hz, 1H), 2.20(m, 1H), 2.15 (s, 3H), 1.84 (m, 2H), 1.66 (m, 1H).

EXAMPLE 24

Repeating the procedure of Example 23, but using the appropriatesubstituted acetylene in place of propargyl alcohol the followingcompounds were obtained:

(a) 5- 4-(2-Hydroxy-3-butynyl)!-3-(1-methyl-2-pyrrolidinyl)pyridinefumarate.

M.p. 132°-133° C. (EtOH); ¹ H NMR (DMSO-d₆, 300 MHz):

δ 8.49 (s, 2H), 7.77 (s, 1H), 6.60 (s, 2H), 4.41 (app. dd, J=14, 7 Hz,1H), 3.29 (app. t, J=8 Hz, 1H), 3.22 (td, J=9, 2 Hz, 1H), 2.35 (app. dd,J=9, 9 Hz, 1H), 2.20 (m, 1H), 2.13 (s, 3H), 1.82 (m, 2H), 1.67 (m, 1H),1.38 (d, J=7 Hz, 3H).

(b) 5- 4-(1-Hydroxy-3-butynyl)!-3-(1-methyl-2-pyrrolidinyl)pyridinefumarate.

M.p. 145°-147° C. (EtOH); ¹ H NMR (DMSO-d₆, 300 MHz): δ 8.50 (S, 1H),8.48 (s, 1H), 7.79 (s, 1H), 6.60 (s, 3H), 3.59 (t, J=7 Hz, 2H), 3.37(app. t, J=8 Hz, 1H), 3.26 (td, J=9, 2 Hz, 1H), 2.58 (t, J=7 Hz, 2H),2.42 (app. dd, J=9, 9 Hz, 1H), 2.23 (m, 1H), 2.17 (s, 3H), 1.84 (m, 2H),1.68 (m, 1H).

(c) 5- 1-(1-Pentynyl)!-3-(1-methyl-2-pyrrolidinyl)pyridine fumarate.

M.p. 105°-107° C. (EtOAc); ¹ H NMR (DMSO-d₆, 300 MHz): δ 8.53 (m, 2H),7.83 (s, 1H), 6.64 (bs, 2H), 3.43 (app. t, J=9 Hz, 1H), 3.32 (app. t,J=8 Hz, 1H), 2.47 (m 3H), 2.25 (m, 1H), 2.23 (s, 3H), 1.92 (m, 2H), 1.75(m, 1H), 1.60 (m, 2H), 1.03 (t, J=8 Hz, 3H).

(d) 5-4-(2-Hydroxy-2-methyl-3-butynyl)!-3-(1-methyl-2-pyrrolidinyl)pyridinefumarate.

M.p. 143°-144° C. (EtOAc); ¹ H NMR (DMSO-d₆, 300 MHz): δ 8.56 (b, 2H),7.81 (s, 1H), 6.64 (s, 2H), 3.39 (app. t, J=8 Hz, 1H), 3.27 (td, J=7, 2Hz, 1H), 2.44 (app. dd, J=8, 8 Hz, 1H), 2.24 (m, 1H), 2.18 (s, 3H), 1.84(m, 2H), 1.71 (m, 1H), 1.48 (s, 6H).

(e) 5-3-(1-Dimethylamino-2-propynyl)!-3-(1-methyl-2-pyrrolidinyl)pyridinefumarate.

M.p. 167°-168° C. (EtOAc); ¹ H NMR (DMSO-d₆, 300 MHz): δ 8.54 (s, 1H),8.50 (s, 1H), 7.80 (s, 1H), 6.60 (s, 3H), 3.57 (s, 2H), 3.25 (m, 1H),3.20 (m, 1H), 2.34 (m, 1H), 2.30 (s, 6H), 2.20 (s, 3H), 2.13 (s, 3H),1.83 (m, 2H), 1.62 (m, 1H).

(f) 5- 3-(1-Methox-2-propynyl)!-3-(1-methyl-2-pyrrolidinlyl)pyridinefumarate

M.p. 116°-118° C. (EtOAc); ¹ H NMR (DMSO-d₆, 300 MHz): δ 8.57 (d, J=2Hz, 1H), 8.54 (d, J=2 Hz, 1H), 7.85 (m, 1H), 6.62 (s, 3H), 4.36 (s, 2H),3.35 (s, 3H), 3.30 (m, 1H), 3.23 (b-td, J=8, 2.5 Hz, 1H), 2.38 (dd, J=9,9 Hz, 1H), 2.21 (m, 1H), 2.15 (s, 3H), 1.84 (m, 2H), 1.69 (m, 1H).

EXAMPLE 25 5- 1-(Propynl)!-3-methyl-2-pyrrolidinyl)pyridine fumarate

A Parr hydrogenation vessel was charged with5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine (1 g, 4.15 mmol), 10%palladium on charcoal (106 mg, 0.1 mmol), copper(I)iodide (38 mg, 0.2mmol), triphenylphosphine (104 mg, 0.4 mmol) and potassium carbonate(1.38 g, 10 mmol), DME (10 mL) and water (10 mL). The vessel wasevacuated and propyne gas was introduced to a pressure of 20 p.s.i. Themixture was agitated and heated at 90° C. for 6 days, readmittingpropyne gas as necessary. Analysis by GC at this stage indicated about40% completion and the cooled mixture was filtered through celite andthe filtrate concentrated in vacuo. The mixture was then acidified with1M HCl (50 mL) and extracted with toluene (50 mL). The aqueous layer wasmade basic with solid potassium carbonate and extracted with ethylacetate (2×100 mL). The combined ethyl acetate extracts were washed withwater (50 mL), dried (MgSO₄) and concentrated to afford an oil. Thecrude product was purified by silica gel column chromatography withethyl acetate:hexane (1:1) as eluant to afford5-propynyl-3-(1-methyl-2-pyrrolidinyl)pyridine (250 mg, 30%). A portion(225 mg) of this material was converted to the title compound by theaddition of one equivalent of fumaric acid to a methanol (10 mL)solution of the free amine at 25° C. After 30 minutes the solvent wasremoved in vacuo and the residue pumped under high vacuum. Triturationwith diethyl ether followed by recrystallization from ethyl acetateafforded 5- 1-(1-propynl)!-3-(1-methyl-2-pyrrolidinyl)pyridine fumarate,180 mg, 50%. M.p. 188°-189° C. (EtOAc); ¹ H NMR (DMSO-d₆, 300 MHz): δ8.49 (s, 1H), 8.47 (s, 1H), 7.77 (s, 1H), 6.60 (s, 2H), 3.34 (t, J=9 Hz,1H), 3.25 (app. t, J=9 Hz, 1H), 2.41 (dd, J=9, 9 Hz, 1H), 2.22 (m, 1H),2.16 (s, 3H), 2.08 (s, 3H), 1.85 (m, 2H), 1.69 (m, 1H).

EXAMPLE 26 5-Bromo-3-(1-tert-butyloxycarbonyl-2-pyrrolidinyl)pyridine

5-Bromo-3-(1-H-pyrrolidinyl)pyridine (4.54 g, 20 mmol), di-tert-butyldicarbonate (4.80 g, 22 mmol) and triethylamine (3.1 mL, 22 mmol) weredissolved in methylene chloride (50 mL) and stirred at 0° C. under adrying tube. 4-Dimethylaminopyridine (122 mg, 1 mmol) was added and themixture was stirred at 25° C. for 18 h. The mixture was concentrated invacuo, then water (20 mL) and methylene chloride (20 mL) were added. Theorganic phase was separated and the aqueous layer washed with methylenechloride (2×20 mL). The combined organic extracts were washed with brine(20 mL) and dried (MgSO₄). The solvents were removed in vacuo and theresidue chromatographed on "flash" silica gel with ethyl acetate:hexane(1:9 to 1:4) as eluants to afford the title compound as an oil, 3.38 g,52%. ¹ H NMR (CDCl₃, 300 MHz): δ 8.55 (b-s, 1H), 8.39 (d, J=2 Hz, 1H),7.64 (b-s, 1H), 4.92 (b-m, 0.5H), 4.76 (b-m, 0.5H), 3.5-3.7 (b-m, 2H),2.39 (b-m, 1H), 1.75-2.0 (m, 3H), 1.46 (s, 3H), 1.22 (s, 6H).

EXAMPLE 27 5-4-(2-Hydroxy-2-methyl-3-butyl)!-3-(1-tert-butyloxycarbonyl-2-pyrrolidinyl)pyridine

A mixture of 5-bromo-3-(1-tert-butyloxycarbonyl-2-pyrrolidinyl)pyridine(1 g, 3.06 mmol), 10% palladium on charcoal (80 mg, 0.077 mmol),copper(I)iodide (58 mg, 0.30 mmol), triphenylphosphine (80 mg, 0.30mmol) and potassium carbonate (1.06 g, 7.65 mmol) in DME (5 mL) andwater (5 mL) was stirred at 25° C. After 0.75 h 2-methyl-3-butyn-2-ol(0.74 mL, 7.65 mmol) was added and the reaction flask was heated at 80°C. for 18 h. Water (30 mL) and ethyl acetate (30 mL) were added to thecooled mixture and this was filtered through celite. The organic phasewas separated and the aqueous layer extracted with ethyl acetate (3×20mL) and the combined ethyl acetate extracts were washed with brine (20mL), dried (MgSO₄) and concentrated in vacuo. The crude product waspurified by silica gel column chromatography with ethyl acetate:hexane(1:3 to 1:1) as eluants to afford5-(2-hydroxy-2-methyl-3-butynyl)-3-(1-tert-butyloxycarbonyl-2-pyrrolidinyl)pyridineas an oil (772 mg, 76%). LRMS (EI) m/e 231 (M⁺ +H--CO₂ and isobutylene),230 (M⁺ --CO₂ and isobutylene), 229 (M⁺ --CO₂ tBu); ¹ H NMR (CDCl₃, 300MHz): δ 8.56 (b-s, 1H), 8.37 (b-d, J=1.5 Hz, 1H), 7.53 (m, 1H), 4.93(b-m, 0.5H), 4.76 (b-m, 0.5H), 3.5-3.7 (b-m, 2H), 2.36 (m, 1H), 1.75-2.0(b-m, 3H), 1.72 (b-s, 1H), 1.63 (s, 6H), 1.45 (b-s, 3H), 1.21 (b-s, 6H).

EXAMPLE 28 5-Ethynyl-3-(1-tert-butyloxycarbonyl-2-pyrrolidinyl)pyridine

5-(2-Hydroxy-2-methyl-3-butynyl)-3-(1-tert-butyloxycarbonyl-2-pyrrolidinyl)pyridine(495 mg, 1.5 mmol) was dissolved in toluene (30 mL) and catalytic sodiumhydride (10 mg) was added. The solution was heated until severalmilliliters of toluene-acetone mixture was removed by distillation. Themixture was cooled to 25° C. and water (20 mL) and ethyl acetate (40 mL)were added. The organic phase was separated and the aqueous layerextracted with ethyl acetate (2×40 mL) and the combined organic extractswere washed with brine (20 mL), dried (MgSO₄) and concentrated in vacuo.The crude product was purified by silica gel column chromatography withethyl acetate:hexane (1:3) as eluant to afford5-ethynyl-3-(1-tert-butyloxycarbonyl-2-pyrrolidinyl)pyridine as an oil(250 mg, 61%). LRMS (EI) m/e 217 (M⁺ +H--isobutylene), 216 (M⁺--isobutylene); ¹ H NMR (CDCl₃, 300 MHz): δ 8.59 (b-s, 1H), 8.42 (d,J=1.5 Hz, 1H), 7.59 (b-s, 1H), 4.94 (b-m, 0.5H), 4.77 (b-m, 0.5H), 3.64(b-m, 2H), 3.21 (s, 1H), 2.39 (m, 1H), 1.75-2.0 (b-m, 3H), 1.46 (s, 3H),1.21 (s, 6H).

EXAMPLE 29 5-Ethynyl-3-(1-H-2-pyrrolidinyl)pyridine fumarate

5-Ethynyl-3-(1-tert-butyloxycarbonyl-2-pyrrolidinyl)pyridine (217 mg,0.8 mmol) was dissolved in a mixture of methylene chloride (9 mL) andtrifluoroacetic acid (6 mL). The solution was stirred for 3 h at 25° C.and then concentrated in vacuo. Methanol (20 mL) and solid potassiumcarbonate were added and the mixture was stirred, filtered andconcentrated. Water (5 mL) and ammonium hydroxide (5 mL) were added andthe aqueous phase was extracted with methylene chloride (5×10 mL). Theorganic extracts were washed with brine (10 mL), dried (MgSO₄) andconcentrated to afford crude product (67 mg). The aqueous phase wasconcentrated in vacuo and extracted with methylene chloride (3×10 mL).The organic extracts were dried (MgSO₄), filtered and concentrated toafford a second crop of product (26 mg). The crude material was combinedand purified by silica gel column chromatography with methanol:methylenechloride (1:19 to 1:9) as eluants to afford5-ethynyl-3-(1-1H-2-pyrrolidinyl)pyridine as an oil (76 mg, 67%). Thiswas converted to the title compound by the addition of one equivalent offumaric acid to a methanol (5 mL) solution of the free amine at 25° C.After 30 minutes the solvent was removed in vacuo and the residue pumpedunder high vacuum. Trituration with diethyl ether followed byrecrystallization from ethyl acetate afforded5-ethynyl-3-(1-H-2-pyrrolidinyl)pyridine fumarate, (123 mg, 97%). M.p.152°-153° C. (EtOAc); ¹ H NMR (DMSO-d₆, 300 MHz): δ 8.65 (d, J=2 Hz,1H), 8.63 (d, J=2 Hz, 1H), 8.02 (t, J=2 Hz, 1H), 6.48 (s, 2H), 4.51 (s,1H), 4.46 (app. t, J=8 Hz, 1H), 3.1-3.3 (m, 1H), 2.30 (m, 1H), 1.80-2.05(m, 2H).

EXAMPLE 30 5-Bromo-3-3,3-dibromo-1-methyl-5-pyrrolidin-2-only)pyridine

To a solution of 5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine (1.57 g,6.5 mmol) in glacial acetic acid (12 mL) and water (3 mL) was addedbromine (2 mL) dropwise at 25° C. Stirring was continued for 18 h andthe solution was then heated at 85° C. for 2 h. Water (30 mL) was addedto the cooled solution and the mixture was adjusted to pH 11 by theaddition of solid potassium carbonate. Ethyl acetate (50 mL) was addedand the organic phase was separated. The aqueous phase was extractedwith ethyl acetate (2×20 mL) and the combined extracts were washed withbrine (20 mL), dried (MgSO₄) and concentrated in vacuo. The crudematerial was chromatographed on silica gel with ethyl acetate:hexane(1:1) as eluant to afford the product as a solid (1.63 g, 60%). M.p.139°-140° C.; ¹ H NMR (DMSO-d₆, 300 MHz): δ 8.73 (d, J=2 Hz, 1H), 8.63(d, J=2 Hz, 1H), 8.20 (t, J=2 Hz, 1H), 4.84 (dd, J=7.5, 6 Hz, 1H), 3.56(dd, J=15, 6 Hz, 1H), 3.04 (dd, J=15, 7.5 Hz, 1H), 2.64 (s, 3H).

EXAMPLE 31 5-Bromo-3-(1-methyl-5-pyrrolidin-2-only)pyridine

Sodium borohydride (862 mg, 22.8 mmol) was dissolved in ethanol (20 mL)and tellurium metal powder (1.45 g, 11.4 mmol) was added in portions.The mixture was heated under reflux for 0.25 h and5-bromo-3-(3,3-dibromo-1-methyl-5-pyrrolidin-2-onyl)pyridine (775 mg,1.9 mmol) was added to the solution at 25° C. After stirring for 2 h,ethyl acetate (50 mL) was added and the solution was filtered throughCelite and concentrated in vacuo. 1M HCl (10 mL) was added to theresidue and the solution was adjusted to pH 11 with solid potassiumcarbonate. After extraction with ethyl acetate (50 mL) the organic phasewas separated. The aqueous phase was extracted with ethyl acetate (2×50mL) and the combined organic phases were washed with brine (30 mL),dried (MgSO₄) and concentrated. This material was chromatographed onsilica gel with ethyl acetate:hexane (1:1) as eluant to afford5-bromo-3-(1-methyl-5-pyrrolidin-2-onyl)pyridine as a solid (329 mg,68%). M.p. 85°-87° C.; ¹ H NMR (CDCl₃, 300 MHz): δ 8.66 (d, J=2 Hz, 1H),8.42 (d, J=2 Hz, 1H), 7.68 (t, J=2 Hz, 1H), 4.56 (t, J=7 Hz, 1H), 2.71(s, 3H), 2.45-2.65 (m, 2H), 1.80-1.95 (m, 2H).

EXAMPLE 32 5-4-2-Hydroxy-2-methyl-3-butynyl)!-3-(1-methyl-5-pyrrolidin-2-only)pyridine

A mixture of 5-bromo-3-(1-methyl-5-pyrrolidin-2-onyl)pyridine (255 mg, 1mmol), 10% palladium on charcoal (26 mg, 0.025 mmol), copper(I)iodide(19 mg, 0.1 mmol), triphenylphosphine (26 mg, 0.1 mmol) and potassiumcarbonate (345 mg, 2.5 mmol) in DME (3 mL) and water (3 mL) was stirredat 25° C. After 0.75 h 2-methyl-3-butyn-2-ol (0.24 mL, 2.5 mmol) wasadded and the reaction flask was heated at 80° C. for 7 h. Water (5 mL)and ethyl acetate (20 mL) were added to the cooled mixture and this wasfiltered through celite. The organic phase was separated and the aqueousphase was extracted with ethyl acetate (3×10 mL). The combined ethylacetate extracts were washed with brine (20 mL), dried (MgSO₄), filteredand concentrated. The crude product was purified by silica gel columnchromatography with ethyl acetate:hexane (1:1) and (3:1) to ethylacetate as eluants to afford 5-4-(2-hydroxy-2-methyl-3-butynyl)!-3-(1-methyl-5-pyrrolidin-2-onyl)pyridineas an oil (227 mg, 88%). LRMS (EI) m/e 259 (M⁺ +H), 258 (M⁺), 257 (M⁺--H); ¹ H NMR (CDCl₃, 300 MHz): δ 8.67 (d, J=2 Hz, 1H), 8.41 (d, J=2 Hz,1H), 7.55 (t, J=2 Hz, 1H), 4.56 (app t, 1H), 2.69 (s, 1H), 2.45-2.65 (m,3H), 1.86 (m, 1H), 1.81 (s, 1.64 (s, 6H).

EXAMPLE 33 5-Ethynyl-3-(1-methyl-5-pyrrolidin-2-onyl)pyridine

5-(2-Hydroxy-2-methyl-3-butynyl)-3-(1-methyl-5-pyrrolidin-2-onyl)pyridine(200 mg, 0.77 mmol) was dissolved in toluene (20 mL) and catalyticsodium hydride (5 mg) was added. The solution was heated until severalmilliliters of toluene-acetone mixture were removed by distillation. Themixture was cooled to 25° C. and water (10 mL) and ethyl acetate (20 mL)were added. The organic phase was separated and the aqueous layerextracted with ethyl acetate (2×20 mL) and the combined organic extractswere washed with brine (10 mL), dried (MgSO₄) and concentrated in vacuo.The crude product was purified by silica gel column chromatography withethyl acetate as eluant to afford5-ethynyl-3-(1-methyl-5-pyrrolidin-2-onyl)pyridine as a solid (125 mg,81%). M.p. 83°-84° C.; ¹ H NMR (CDCl₃, 300 MHz): δ 8.69 (d, J=2 Hz, 1H),8.46 (d, J=2 Hz, 1H), 7.62 (t, J=2 Hz, 1H), 4.57 (dd, J=7, 6 Hz, 1H),3.28 (s, 1H), 2.70 (s, 3H), 2.45-2.65 (m, 3H), 1.88 (m, 1H).

EXAMPLE 34 1,10-Bis-5-3-(1-methyl-2-pyrrolidinyl)pyridine!deca-1,9-diyne fumarate

A mixture of 5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine (1.2 g, 5mmol), 10% palladium on charcoal (160 mg, 0.15 mmol), copper(I)iodide(57 mg, 0.3 mmol), triphenylphosphine (157 mg, 0.6 mmol) and potassiumcarbonate (1.73 g, 12.5 mmol) in DME (10 mL) and water (5 mL) wasstirred at 25° C. After 1 h 1,9-decadiyne (335 mg, 2.5 mmol) was addedand the reaction flask was heated at 80° C. for 18 h. The cooled mixturewas then filtered through celite and the filtrate concentrated in vacuo.The mixture was then acidified with 1M HCl (50 mL) and extracted withtoluene (50 mL). The aqueous layer was made basic with solid potassiumcarbonate and extracted with ethyl acetate (2×100 mL). The combinedethyl acetate extracts were washed with water (50 mL), dried (MgSO₄) andconcentrated. The crude product was purified by silica gel columnchromatography with methanol: methylene chloride (1:19) as eluant toafford the product as an oil (710 mg, 63%). This material (690 mg) wasconverted to the title compound by the addition of two equivalents offumaric acid to a methanol (10 mL) solution of the free amine at 25° C.After 30 minutes the solvent was removed in vacuo and the residue pumpedunder high vacuum. Trituration with diethyl ether followed byrecrystallization from ethyl acetate afforded 1,10-bis-5-3-(1-methyl-2-pyrrolidinyl)pyridine!deca-1,9-diyne fumarate, 420 mg,31%. M.p. 170°-172° C. (EtOAc); ¹ H NMR (CD₃ OD, 300 MHz): δ 8.70 (BS,4H), 7.93 (s, 2H), 6.55 (s, 8H), 4.16 (app. t, J=9 Hz, 2H), 3.66 (m,2H), 3.06 (m, 2H), 2.54 (s, 6H), 2.33 (m, 6H), 2.11 (s, 6H), 1.46 (m,4H), 1.35 (m, 4H).

EXAMPLE 35 Enantiomerically enriched 5-bromo-3-(2-pyrrolidinyl)pyridine

Carbobenzyloxy-L-proline (37.4 g, 150 mmol) was dissolved in DME (100mL) and cooled to 0° C. with stirring. Sodium borohydride (1.89 g, 50mmol) was added in portions (gas evolution) and the resulting mixturewas stirred for 2 h at 25° C. affording a colorless solution. Thesolvents were removed in vacuo and the resulting gum dissolved inmethylene chloride (50 mL). To this solution was added a mixture of5-bromo-3-(2-pyrrolin-1-yl)pyridine (5.63 g, 25 mmol) andcarbobenzyloxy-L-proline (6.23 g, 25 mmol) in methylene chloride (50 mL)and this was stirred at 25° C. for 36 h. The solvent was removed invacuo and 6M HCl (200 mL) was added to the residue. The resultingsolution was extracted with isopropyl acetate (200 mL) and the phasesseparated. The acidic aqueous phase was basified with solid NaOH to pH14 and then extracted with methylene chloride (3×200 mL). The combinedmethylene chloride extracts were washed with brine (150 mL), dried(MgSO₄) and concentrated in vacuo. The crude product was chromatographedon silica gel with ethyl acetate, then methanol:ethyl acetate (1:19 to1:9) as eluants to afford 5-bromo-3-(2-pyrrolidinyl)pyridine (4.1 g,72%) obtained as a pale yellow oil. LRMS (EI) m/e 227 (C₉ H₁₁ N₂ ⁸¹Br--H⁺), 225 (C₉ H₁₁ N₂ ⁷⁹ Br--H⁺); ¹ H NMR (DMSO-d₆, 300 MHz) δ 8.53(d, J=2.2 Hz, 1H), 8.49 (d, J=1.8 Hz, 1H), 7.91 (t, J=2.0 Hz, 1H), 4.17(t, J=7.7 Hz, 1H), 3.18 (m, 1H), 3.06 (m, 1H), 2.00 (m, 1H), 2.07 (s,1H), 2.00-1.77 (m, 2H), 1.63 (m, 1H).

The enantiomeric enrichment of this material (30% ee) was assessed using¹ H NMR with (R)-(+)-α-methoxy-α-(trifluoromethyl)phenylacetic acid as achiral shift reagent.

EXAMPLE 36 Enantiomerically enriched 5-bromo-3-1-methyl-2-pyrrolidinyl)pyridine

Enantiomerically enriched 5-bromo-3-(2-pyrrolidinyl)pyridine (1.82 g, 8mmol) was dissolved in a mixture of 98% formic acid (16 mL) and 37%aqueous formaldehyde (8 mL). The solution was heated with stirring for 3h at 80° C. After cooling to 25° C. the mixture was concentrated invacuo and water (30 mL) added. The mixture was basified with solid NaOHto pH 12 and extracted with methylene chloride (3×40 mL). The combinedorganic extracts were washed with brine (20 mL), dried (MgSO₄) andconcentrated in vacuo. The crude material was chromatographed on silicagel with ethyl acetate:hexane (1:3) as eluant to afford5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine as an oil, 1.63 g,84%. LRMS(EI) m/e 242 (C₁₀ H₁₃ N₂ ⁸¹ Br), 241 (C₁₀ H₁₃ N₂ ⁷⁹ Br--⁺ H), 240 (C₁₀H₁₃ N₂ ⁷⁹ Br), 239 (C₁₀ H₁₃ N₂ Br--⁺ H); ¹ H NMR (DMSO-d₆, 300 MHz) δ8.55 (d, J=2.1 Hz, 1H), 8.44 (d, J=1.9 Hz, 1H), 7.88 (t, J=1.9 Hz, 1H),3.24 (b-dt, J=8.1 Hz, 1H), 3.10 (t, J=8.0 Hz, 1H), 2.36 (m, 1H), 2.18(s, 3H), 1.95 (m, 1H), 1.85 (m, 1H), 1.70 (m, 1H).

A portion of this material (482 mg) was treated withdi-p-toluoyl-D-tartaric acid monohydrate (534 mg) and recrystallizedfrom ethanol-ethyl acetate (1:4) to afford5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine of approximately 90% ee asdetermined by chiral GC. This material, as the free amine, waselaborated as described in Example 37.

EXAMPLE 37

Repeating the procedure of Example 23 but using 2-methyl-3-butyn-2-olinplace of propargyl alcohol the following enantiomerically enrichedcompound was obtained:

5- 4-(2-Hydroxy-2-methyl-3-butynyl)!-3-(1-methyl-2-pyrrolidinyl!pyridine

M.p. 79°-81° C. (Cyclohexane); ¹ H NMR (CDCl₃, 300 MHz): δ 8.65 (d, J=2Hz, 1H), 8.41 (d, J=2 Hz, 1H), 7.80 (t, J=2 Hz, 1H), 4.71 (bs, 1H), 3.24(app. td, J=7,2 Hz, 1H), 3.07 (app. t, J=9 Hz, 1H), 2.31 (app. dd, J=9,9 Hz, 1H), 2.19 (m, 1H), 2.16 (s, 3H), 1.9-2.1 (m, 1H), 1.77-1.90 (m,1H), 1.65-1.77 (m, 1H), 1.62 (s, 6H).

EXAMPLE 38

Repeating the procedure of Example 28 but using 5-4-(2-hydroxy-2-methyl-3-butynyl)!-3-(1-methyl-2-pyrrolidinyl)pyridine inplace of 5-(2-hydroxy-2-methyl-3-butynyl)-3-(1-tert-butyloxycarbonyl-2-pyrrolidinyl)pyridine the following product wasobtained:

5-Ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine

LRMS (EI) m/e 187 (M³⁰ +H), 186 (M³⁰ ), 185 (M⁺ --H); ¹ H NMR (CDCl₃,300 MHz): δ 8.58 (d, J=2 Hz, 1H), 8.48 (d, J=2 Hz, 1H), 7.80 (app. t,J=2 Hz, 1H), 3.23 (t, J=8 Hz, 1H), 3.18 (s, 1H), 3.08 (app. t, J=8.5 Hz,1H), 2.30 (dd, J=9, 9 Hz, 1H), 2.21 (m, 1H), 2.16 (s, 3H), 1.65-2.00 (m,3H).

A portion of this material (248 mg) was treated withdi-p-toluoyl-D-tartaric acid monohydrate (485 mg) and recrystallizedfrom ethanol to afford5-ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridinedi-p-toluoyl-D-tartrate(452 mg, 66%). M.p. 163°-164° C. (EtOH); ¹ H NMR (DMSO-d₆, 300 MHz): δ8.66 (d, J=2 Hz, 1H), 8.63 (d, J=2 Hz, 1H), 7.99 (t, J=2 Hz, 1H), 7.88(d, J=8 Hz, 2H), 7.37 (d, J=8 Hz, 2H), 5.74 (s, 2H), 4.48 (s, 1H), 3.8(b-m, 1H), 3.4 (b-m, 1H), 2.73 (dd, J=9, 9 Hz, 1H), 2.39 (s, 6H), 2.35(s, 3H), 2.3 (m, 1H), 1.8-2.0 (m, 3H).

This product possessed a 97% enantiomeric excess as determined by chiralGC.

EXAMPLE 39

Repeating the procedures of Example 36 to Example 38 but using theappropriate compounds of opposite configuration the following productwas obtained:

5-Ethynl-3-(1-methyl-2-pyrrolidinyl)pyridine di-p-toluoyl-L-tartrate

M.p. 158°-159° C. (EtOH); ¹ H NMR (DMSO-d₆, 300 MHz): δ 8.65 (d, J=2 Hz,1H), 8.60 (d, J=2 Hz, 1H), 7.97 (t, J=2 Hz, 1H), 7.87 (d, J=8 Hz, 2H),7.36 (d, J=8 Hz, 2H), 5.74 (s, 2H), 4.50 (s, 1H), 3.71 (m, 1H), 3.39 (m,1H), 2.65 (dd, J=9, 9 Hz, 1H), 2.38 (s, 6H), 2.29 (s, 3H), 2.23 (m, 1H),1.75-1.95 (m, 3H).

This product possessed a 95% enantiomeric excess as determined by chiralGC.

EXAMPLE 40 Radioligand Binding

³ H-Nicotine binding to rat cerebral membranes was performed accordingto modifications of the method of Flyn and Mash (J. Neurochem. 47:1948(1986)). ³ H-Nicotine (80 ci/mmol; New England Nuclear Corporation,Boston, MA) was used as the ligand for nicotinic acetylcholine receptorbinding assays. All other reagents were purchased from the SigmaChemical Co. (St. Louis, Mo.).

Male Spmgue-Dawley rats (250-400 gm) were sacrificed by decapitation,the brains removed and the cerebral cortex dissected on ice. Synapticmembranes were prepared by homogenizing the cortical tissue in 20volumes of ice-cold modified Tris buffer (50mM Tris pH 7.4, 120mM NaCl,5 mM KCl, 2 mM EDTA, 1 mM PMSF) with a polytron (20 sec at setting 5-6)followed by centrifugation (15 min at 25,000×g) at 4° C. The resultantpellet was rehomogenized and centrifuged twice. The final pellet wasresuspended in ice-cold assay buffer (50 mM Tris pH 7.4, 120 mM NaCl, 5mM KCl, 2 mM CaCl₂, 1 mM MgCl₂) at a concentration of membraneequivalent to 1 gm wet weight cortex per 10 ml buffer. After proteindetermination the final membrane preparation was diluted with buffer to3 mg protein/ml. This membrane preparation was used in either the freshstate or frozen (-70° C.) then thawed.

The binding assay is performed manually using 96-well plates, or using aBiomek automated work station (Beckman Instrument Co.). ³ H-Nicotine wasdiluted in assay buffer to give a final concentration of 1.9 nM. TheBiomek automated work station was programmed to automatically transfer750 μl of assay buffer with ³ H-nicotine, 230 μl of membrane preparationand 20 μl of solution containing the compound of interest in assaybuffer, DMSO, ethanol:DMSO (1:1) or appropriate vehicle to the 96-wellplate. Atropine was added to the incubation buffer at a finalconcentration of 3 μM to block binding to muscarinic acetylcholinereceptor sites. The plates were maintained on ice for 60 min and thetissue-bound radioactivity was separated from the free by rapidfiltration in a Brandel Harvester onto GF/C filters presoaked in 0.5%polyethyleneimine for at least 2 hr. The filters were washed with 4×2 mlof ice-cold assay buffer and filters were transferred to vials to which4 ml of scintillation cocktail was added. The radioactivity was measuredin a LS-6500 Beckman Liquid Scintillation Counter in an autodpm mode.Data were analyzed by log-logit transformation or non-linear regressionanalysis (e.g., employing GraphPad Prism, available from GraphPadSoftware, San Diego, Calif.) to give IC₅₀ values. Non-specific bindingwas defined by 10 μM cytisine.

The ability of invention compounds to displace ³ H-QNB (quinuclidinylbenzilate; 43 Ci/mmol, 60 pM) from muscarinic acetylcholine receptors inrat cerebral membranes can also be tested using the above-describedmethod in which ³ H-nicotine is replaced with any radiolabeledacetylcholine receptor ligand.

The results of ³ H-nicotine and ³ H-QNB binding/displacment assays ofseveral invention compounds are summarized in Table I.

                  TABLE I                                                         ______________________________________                                                       IC.sub.50 (μM)                                              Compound Tested, Formula    Quinuclidinyl                                     I, wherein . . . Nicotine   benzilate                                         ______________________________________                                        A.sub.2 = CH.sub.2 ; B = CH.sub.2 ;                                                             0.047     9.5                                               R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 4-biphenyl                                                          A.sub.2 = CH.sub.2 ; B = CH.sub.2 ;                                                             0.028     >10                                               R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 3-chloro-4-hydroxyphenyl                                            A.sub.2 = CH.sub.2 ; B = CH.sub.2 ;                                                             0.031     14                                                R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 4-methylphenyl                                                      A.sub.2 = CH.sub.2 ; B = CH.sub.2 ;                                                             0.018     37.7                                              R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 4-methoxyphenyl                                                     A.sub.2 = CH.sub.2 ; B = CH.sub.2 ;                                                             0.0054    19.1                                              R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 4-hydroxyphenyl                                                     A.sub.2 = CH.sub.2 ; B = CH.sub.2 ;                                                             0.12      3.7                                               R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 3-chlorophenyl                                                      A.sub.2 = CH.sub.2 ; B = CH.sub.2 ;                                                             0.49      24.9                                              R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = H;                                                                  R.sup.5 = 4-fluorophenyl                                                      A.sub.2 = CH.sub.2 ; B = CH.sub.2 ;                                                             0.0046    10.1                                              R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = ethynyl (racemic)                                                   A.sub.2 = CH.sub.2 ; B = CH.sub.2 ;                                                             0.029     35                                                R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 3-fluoro-4-hydroxyphenyl                                            A.sub.2 = CH.sub.2 ; B = CH.sub.2 ;                                                             0.027     30.5                                              R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 3-fluoro-4-methoxyphenyl                                            A.sub.2 = CH.sub.2 ; B = CH.sub.2 ;                                                             0.0036    >100                                              R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 5-(1-hydroxy-2-                                                     propynyl)                                                                     A.sub.2 = CH.sub.2 ; B = CH.sub.2 ;                                                             0.011     >100                                              R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 5-(2-hydroxy-3-                                                     butynyl)                                                                      A.sub.2 = CH.sub.2 ; B = CH.sub.2 ;                                                             0.006     >100                                              R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 5-(1-hydroxy-3-                                                     butynyl)                                                                      A.sub.2 = CH.sub.2 ; B = CH.sub.2 ;                                                             0.042     39                                                R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 5(1-pentynyl)                                                       A.sub.2 = CH.sub.2 ; B = CH.sub.2 ;                                                             0.038     >100                                              R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 5-(2-hydroxy-2-methyl-3-                                            butynyl)                                                                      A.sub.2 = CH.sub.2 ; B = CH.sub.2 ;                                                             0.025     100                                               R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 5-(1-dimethylamino-2-                                               propynyl)                                                                     A.sub.2 = CH.sub.2 ; B = CH.sub.2 ;                                                             0.0026    >100                                              R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 5-(1-methoxy-2-propynyl)                                            A.sub.2 = CH.sub.2 ; B = CH.sub.2 ;                                                             0.029     >100                                              R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 5-(1-propynyl)                                                      A.sub.2 = CH.sub.2 ; B = CH.sub.2 ;                                                             0.058     8.9                                               R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 5-(1-ethynyl)                                                       A.sub.2 = CH.sub.2 ; B = CH.sub.2 ;                                                             >100      >100                                              R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 5-(1-ethynyl)                                                       A.sub.2 = CH.sub.2 ; B = CH.sub.2 ;                                                             0.0026    n.d.                                              R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 5-(1-ethynyl)                                                       Di-p-toluoyl-L-tartrate                                                       A.sub.2 = CH.sub.2 ; B = CH.sub.2 ;                                                             0.078     4.7                                               R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 5-(1-ethynyl)                                                       Di-p-toluoyl-D-tartrate                                                       A.sub.2 = CH.sub.2 ; B = CH.sub.2 ;                                                             0.052     7.5                                               R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sub.5 = See below*                                                          ______________________________________                                         *R.sup.5 = 5 1(10- 5(3- 1methyl-2-pyrrolidinyl!pyridine)deca-1,9-diynyl  

As evidenced by the IC₅₀ values in the Table, each of the compoundstested was able to displace acetylcholine receptor ligands from theirbinding sites in rat cerebral membranes.

EXAMPLE 41 Neurotransmitter Release

Measurement of ³ H-dopamine release from rat striatal slices wasperformed according to the method of Sacaan et al. (J. Neurochem. 59:245(1992)). Male Sprague-Dawley rats (250-300 g) were decapitated and thestriata or olfactory tubercles dissected quickly on a cold glasssurface. The tissue was chopped to a thickness of 300 μm with a McIlwaintissue chopper. After chopping again at right angles the tissue wasdispersed and incubated for 10 min. at 37° C. in oxygenated Kreb'sbuffer. ³ H-Dopamine (40 Ci/mmol, NEN-Dupont, Boston, Mass.) was added(50 nM) and the tissue was incubated for 30 min. in Kreb's buffercontaining 10 μM pargyline and 0.5 mM ascorbic acid. Aliquots of theminced tissue were then transferred to chambers of a Brandel Superfusionsystem in which the tissue was supported on Whatman GF/B filter discs.The tissue was then superfused with buffer at a constant flow rate of0.3 ml/min by means of a Brandel peristaltic pump. The perfusate wascollected in plastic scintillation vials in 3-min fractions, and theradioactivity was estimated by scintillation spectrophotometry. Thesuperfusate for the first 120 min was discarded. After two baselinefractions had been collected, the superfusion buffer was switched tofresh buffer with or without compound of interest. At the end of theexperiment the filter and the tissue were removed, and the radiolabeledneurotransmitter content was estimated after extraction intoscintillation fluid. The fractional efflux of radiolabeledneurotransmitter was estimated as the amount of radioactivity in theperfusate fraction relative to the total amount in the tissue.

Following essentially the same procedure as set forth above, the amountof ³ H-norepinephrine released from rat hippocampus, thalamus andprefrontal cortex slices superfused with buffer containing (or lacking)compounds of interest was also measured.

Results of studies of the effects of an invention compound (as comparedto the effect of nicotine) on the release of neurotransmitters from ratbrain slices are presented in Table II. Results presented in Part A ofthe Table are expressed as the percent fractional release and resultspresented in Part B of the Table are expressed as a percentage, relativeto nicotine response.

                                      TABLE II                                    __________________________________________________________________________    Part A                                                                        Ligand-stimulated .sup.3 H-neurotransmitter Release                           in vitro from Slices of Different Rat Brain Regions                                                                 .sup.3 H-Norepinephrine                                                                .sup.3 H-Dopamine              Ligand or Compound Tested,                                                                 .sup.3 H-Dopamine                                                                    .sup.3 H-Norepinephrine                                                                .sup.3 H-Norepinephrine                                                                Prefrontal                                                                             Olfactory                      Formula I, wherein . . .                                                                   Striatum                                                                             Hippocampus                                                                            Thalamus Cortex   Tubercles                      __________________________________________________________________________    Nicotine     1.84.sup.a                                                                           6.19.sup.b                                                                             1.83.sup.a                                                                             2.32.sup.b                                                                             5.61.sup.a                     A = CH.sub.2 ; B = CH.sub.2 ;                                                              2.2    2.9      1.1      3.4      6.3                            R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 4-biphenyl (300 μM)                                              A = CH.sub.2 ; B = CH.sub.2 ;                                                              8.34   2.5      3.23     2.94     11.4                           R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 3-chloro-4-                                                         hydroxyphenyl (300 μM)                                                     A = CH.sub.2 ; B = CH.sub.2 ;                                                              0.74   0.52     0.31     NT.sup.c 1.0                            R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 4-methylphenyl (300 μM)                                          A = CH.sub.2 ; B = CH.sub.2 ;                                                              2.1    0.99     0.52     1.04     4.0                            R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7,= CH.sub.3 ;                                                          R.sup.5 = 4-methyoxyphenyl                                                    (300 μM)                                                                   A = CH.sub.2 ; B = CH.sub.2 ;                                                              3.73   3.03     2.3      3.16     6.62                           R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 4-hydroxyphenyl                                                     (300 μM)                                                                   A = CH.sub.2 ; B = CH.sub.2 ;                                                              2.0    1.45     1.48     1.7      3.25                           R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 3-chlorophenyl (300 μM)                                          A = CH.sub.2 ; B = CH.sub.2 ;                                                              1.96   0.58     0.9      1.23     2.68                           R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 4-fluorophenyl (300 μM)                                          A = CH.sub.2 ; B = CH.sub.2 ;                                                              2.56   0.69     0.31     0.97     6.68                           R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = ethynyl (300 μM)                                                 A = CH.sub.2 ; B = CH.sub.2 ;                                                              3.33   1.47     NTC      1.14     7.07                           R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 3-fluoro-4-hydroxy-                                                 phenyl (300 μM)                                                            A = CH.sub.2 ; B = CH.sub.2 ;                                                              3.1    0.73     1.75     2.0      2.3                            R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 3-fluoro-4-methoxy-                                                 phenyl (300 μM)                                                            __________________________________________________________________________     .sup.a Nicotine concentration was 100 μM.                                  Nicotine concentration was 300 μM.                                         .sup.c NT = not tested.                                                  

                  TABLE II                                                        ______________________________________                                        Ligand-stimulated Neurotransmitter Release Data                                           % of Nicotine Response.sup.a                                      Ligand or Compound Tested                                                                    ##STR9##                                                                                  ##STR10##                                          ______________________________________                                        Nicotine      100 (10 μM)                                                                            100 (300 μM)                                     A = CH.sub.2 ; B = CH.sub.2 ;                                                               156.8        39.0                                               R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 5- 3-(1-hydroxy-2-                                                  propynyl)!                                                                    A = CH.sub.2 ; B = CH.sub.2 ;                                                                98.0        30.5                                               R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 5- 3-(2-hydroxy-3-                                                  butynyl)!                                                                     A = CH.sub.2 ; B = CH.sub.2 ;                                                               100.0        36.3                                               R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 5- 3-(1-hydroxy-3-                                                  butynyl)!                                                                     A = CH.sub.2 ; B = CH.sub.2 ;                                                                27.7       n.d..sup.b                                          R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 5-(1-pentynyl)                                                      A = CH.sub.2 ; B = CH.sub.2 ;                                                               118.3        18.3                                               R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 5- 4-(2-hydroxy-2-                                                  methyl-3-butynyl)                                                             A = CH.sub.2 ; B = CH.sub.2 ;                                                               235.2       n.d.                                                R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 5- 3-(1-dimethyl-                                                   amino-2-propynyl)!                                                            A = CH.sub.2 ; B = CH.sub.2 ;                                                                61.7        7.4                                                R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 5- 3-(1-methoxy-2-                                                  propynyl)!                                                                    A = CH.sub.2 ; B = CH.sub.2 ;                                                                61.7        13.4                                               R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = H;                                                                  R.sup.5 = 5-(1-ethynyl)                                                       A = CH.sub.2 ; B = CH.sub.2 ;                                                               155.sup.c    17.4                                               R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 5-(1-ethynyl)                                                       Di-p-toluoyl-L-tartrate                                                       A = CH.sub.2 ; B = CH.sub.2 ;                                                                33          3.7                                                R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 5-(1-ethynyl)                                                       Di-p-toluoyl-D-tartrate                                                       ______________________________________                                         .sup.a All compounds were tested at 300 μM, unless noted otherwise.        .sup.b n.d. = not determined                                                  .sup.c Nicotine concentration was 300 μM                              

As shown in Table II, invention compound selectively induces release ofcatecholamines in different brain regions.

EXAMPLE 42 6-Hydroxydopamine Lesion Model of Parkinsonism

Selective lesions of the brain dopamine pathway using the neurotoxin6-hydroxydopamine (6-OHDA) in rats can be used as an experimentalapproach to Parkinson's disease. Unilateral lesions of the nigrostriataldopamine pathway induce a postural asymmetry which becomes manifested asrotation when the animals are activated by dopamine releasers ordopamine agonists. When amphetamine and other stimulant drugs thatinduce pre-synaptic release of dopamine from intact nerve terminals areadministered, the rats rotate in a direction ipsilateral to the lesion.In contrast, when the rats are injected with post-synaptic dopaminereceptor agonists, such as apomorphine, they turn in a contralateraldirection, due to the development of supersensitive dopamine receptorsin the lesioned side. Thus, the 6-OHDA model can be used to determine ifa suspected dopaminergic agent is active, and to differentiate whethersuch action is pre- or post-synaptic.

The effects of invention compounds on rotational behavior in6-hydroxydopamine denervated rats were evaluated using the procedure ofUngerstedt and Arbutknott, Brain Res. 24:485-493 (1970). MaleSpmgue-Dawley rats (Zivic Miller) weighing 170-200 gm were used in the6-OHDA procedure. The ascending nigrostriatal dopamine pathway waslesioned by unilateral stereotaxic injection of 6-OHDA (8.0 μg) into onesubstantia nigra. Allinjections of 6-OHDA were preceded bydesmethylimipramine (25 mg/kg i.p.) and pargyline (75 mg/kg i.p.)approximately 30 minutes prior to undergoing stereotaxic surgery for6-OHDA infusion into the substantia nigra. After one week of recoveryfrom surgery, the effectiveness of the lesions was verified by notingthe response of the animals to apomorphine (0.2 mg/kg, s.c.). Only ratswith a minimum rate of 80 contralateral turns per 30 minutes (a sign ofmore than 80-90% dopamine depletion after a 6-OHDA lesion) were used.Two weeks later, the selected rats were tested with invention andreference compounds using an automated rotometer system to record thenumber and direction of rotations. In order to distinguish spontaneous(non-specific) rotations from induced rotations (specific to the effectof the drug), each rat was used as its own control, employing thefollowing procedure:

The rat was placed in the rotometer system for acclimatation for 15minutes, the vehicle administered subcutaneously, the rat's rotationsrecorded for one hour, then test compound was administered s.c. androtations again recorded for one hour. The number of ipsilateralrotations induced by vehicle was then compared to the number ofipsilateral rotations induced by test compound. Statistical analysis ofthe data was carried out using Student's t-test (paired).

The results of one such study are shown in Table III. Results arereported as the percentage change of ipsilateral rotations, relative tocontrol, per one hour interval. No contralateral rotations were observedwith the tested compounds.

                  TABLE III                                                       ______________________________________                                        Induction of turning in rats with unilateral                                  6-hydroxydopamine lesions of the nigrostriatal                                dopamine pathway                                                                                  Percent change                                            Ligand or Compound Tested                                                                         from control.sup.a                                        ______________________________________                                        Nicotine (1 mg/kg salt, s.c.)                                                                     +357                                                      Amphetamine (1 mg/kg base, s.c.)                                                                  +487                                                      Compound I (20 mg/kg), wherein                                                                    +406                                                      A = CH.sub.2, B = CH.sub.2,                                                   R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H                              R.sup.7 = CH.sub.3                                                            R.sup.5 = ethynyl                                                             Compound I (20 mg/kg), wherein                                                                    -3                                                        A = CH.sub.2, B = CH.sub.2,                                                   R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H                              R.sup.7 = CH.sub.3                                                            R.sup.5 = 3-fluoro-4-methoxyphenyl                                            Compound I (20 mg/kg), wherein                                                                    -40                                                       A = CH.sub.2, B = CH.sub.2,                                                   R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H                              R.sup.7 = CH.sub.3                                                            R.sup.5 = 3-chloro-4-hydroxyphenyl                                            Compound I (20 mg/kg), wherein                                                                    +62                                                       A = CH.sub.2, B = CH.sub.2,                                                   R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H                              R.sup.7 = CH.sub.3                                                            R.sup.5 = 3-chlorophenyl                                                      ______________________________________                                         .sup.a n = 6-18 rats per group                                           

As shown in Table III, invention compounds may induce significantturning towards the lesioned side. The direction of the rotationssuggest increased release of dopamine from the remaining dopamine nerveterminals in the non-lesioned side of the brain. These data areconsistent with in vitro release of ³ H-dopamine from rat striatalslices (see Example 41).

EXAMPLE 43 Locomotor Activity Assay

The effects of invention compounds on locomotor activity of rats wereevaluated using the procedure of O'Neill et al. Psychopharmacology104:343-350 (1991). This assay can be used to assess the primary effectof a compound on general motor activity. A decrease in locomotoractivity is indicative of a possible sedative effect on the animal,whereas an increase in locomotor activity is indicative of a stimulanteffect on the animal.

Locomotor activity of rats (male Sprague-Dawley (Harlan) weighing200-250 gm) was measured for 2 hrs in photocell cages immediately afteradministration of the invention compound. Prior to the test day, theanimals were placed in the activity cages for 3 hrs to familiarize themwith the experimental environment. On the test day, the animals wereplaced in the photocell cages and then injected with compound 1.5 hrslater.

The photocell cages were standard rodent cages (30 cm×20 cm×40 cm) withfour infrared beams crossing the long axis. The animals were under nomotivational constraints and were free to move around. Movements fromone infrared beam to another (ambulation) were called "crossover";successive interruptions of the same beam (vertical and other movementssuch as grooming) were called "general activity."

The results of one such study are shown in Table IV. Results arereported as the percent of change from control values (i.e., salineinjection) for two post-injection periods: 0-60 minutes and 60-120minutes, respectively.

                  TABLE IV                                                        ______________________________________                                        Locomotor activity assay with various invention compounds                                  General Activity.sup.a                                                                   Ambulation.sup.a                                                   (beam breaks)                                                                            (cross overs)                                                        0-60     60-120  0-60   60-120                                 Ligand or Compound Tested                                                                    min      min     min    min                                    ______________________________________                                        Nicotine (1 mg/kg salt,                                                                      +27%     +71%    +169%  +163%                                  s.c.)                                                                         Amphetamine (0.5 mg/kg                                                                       +1112%   +456%   +2598% +1217%                                 salt, s.c.)                                                                   Compound I.sup.b wherein                                                                     -17%     +98     -9%    +73%                                   A = CH.sub.2 ; B = CH.sub.2 ;                                                 R.sup.2, R.sup.4, R.sup.6, R.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 4-biphenyl                                                          Compound I.sup.b wherein                                                                     +3%      -11%    +7%    -16%                                   A = CH.sub.2 ; B = CH.sub.2 ;                                                 R.sup.2, R.sup.4, R.sup.6, F.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = phenylethynyl                                                       Compound I.sup.b wherein                                                                     +63%     +26%    +49%   -14%                                   A = CH.sub.2 ; B = CH.sub.2 ;                                                 R.sup.2, R.sup.4, R.sup.6, F.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 3-fluoro-4-                                                         hydroxyphenyl                                                                 Compound I.sup.b wherein                                                                     +83%     +22%    +58%   +31%                                   A = CH.sub.2 ; B = CH.sub.2 ;                                                 R.sup.2, R.sup.4, R.sup.6, F.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 4-methyoxyphenyl                                                    Compound I.sup.b wherein                                                                     96%      +7%     +74%   +110%                                  A = CH.sub.2 ; B = CH.sub.2 ;                                                 R.sup.2, R.sup.4, R.sup.6, F.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 4-hydroxyphenyl                                                     Compound I.sup.b wherein                                                                     +70%     +220%   +48%   +268%                                  A = CH.sub.2 ; B = CH.sub.2 ;                                                 R.sup.2, R.sup.4, R.sup.6, F.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 3-chlorophenyl                                                      Compound I.sup.b wherein                                                                     +509%    +628%   +631%  +1252%                                 A = CH.sub.2 ; B = CH.sub.2 ;                                                 R.sup.2, R.sup.4, R.sup.6, F.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = ethynyl                                                             Compound I.sup.b wherein                                                                     +95%     +173%   +21%   +14%                                   A = CH.sub.2 ; B = CH.sub.2 ;                                                 R.sup.2, R.sup.4, R.sup.6, F.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 4-fluorophenyl                                                      Compound I.sup.b wherein                                                                     +78%     +202%   +58%   +268%                                  A = CH.sub.2 ; B = CH.sub.2 ;                                                 R.sup.2, R.sup.4, R.sup.6, F.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 3-fluoro-4-                                                         methoxyphenyl                                                                 Compound I.sup.b wherein                                                                     +68%     -17%    +63%   -36%                                   A = CH.sub.2 ; B = CH.sub.2 ;                                                 R.sup.2, R.sup.4, R.sup.6, F.sup.9, R.sup.9a = H;                             R.sup.7 = CH.sub.3 ;                                                          R.sup.5 = 3-chloro-4-                                                         hydroxyphenyl                                                                 ______________________________________                                         .sup.a n = 8 animals per group except for the amphetamine group, for whic     n = 3                                                                         .sup.b Dosage is 20 mg/kg, s.c.                                          

As shown in Table IV, invention compounds may induce an increase inlocomotor activity of rats.

While the invention has been described in detail with reference tocertain preferred embodiments thereof, it will be understood thatmodifications and variations are within the spirit and scope of thatwhich is described and claimed.

That which is claimed is:
 1. A method for treating cognitivedysfunction, said method comprising administering a therapeuticallyeffective amount of a compound having the structure I to a patientsuffering from cognitive dysfunction, wherein structure I is as follows:##STR11## wherein: A is a 1, 2 or 3 atom bridging species which formspart of a saturated or monounsaturated 5-, 6- or 7-membered ringincluding N⁷, C⁸, C₉ and B;B is selected from --O--, --S--, --NR¹⁰ --,wherein R¹⁰ is selected from hydrogen, lower alkyl, aryl, substitutedaryl, alkylaryl, substituted alkylaryl, arylalkyl, substitutedarylalkyl; --C¹⁰ HR^(10a) --, wherein R^(10a) is selected from hydrogen,lower alkyl, hydroxyalkyl, aryl, aryloxyalkyl, fluoro, trifluoromethyl,cyano, cyanomethyl, --OR', --NR'₂, or --SR', wherein each R' isindependently hydrogen, lower alkyl, alkenyl, alkynyl or aryl, provided,however, that neither the --NR'₂ nor the --SR' functionality isconjugated with an alkenyl or alkynyl functionality; or B is ═C¹⁰R^(10a) -- or ═N--, provided there is no double bond in the ring betweenA and B, or between B and C⁹ when there is a double bond between N⁷ andC⁸, and provided that B is not a heteroatom when A is a 1 atom bridgingspecies; R², R⁴, R⁵ and R⁶ are each independently selected fromhydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl,substituted arylalkyl, heterocyclic, substituted heterocyclic,trifluoromethyl, halogen, cyano, nitro;--S(O)R', --S(O)₂ R' or --S(O)₂NHR', wherein each R' is as defined above, provided, however, that whenR², R⁴, R⁵ or R⁶ is --S(O)R', R' is not hydrogen, alkenyl or alkynyl,and provided that when R², R⁴, R⁵ or R⁶ is S(O)₂ NHR', R' is not alkenylor alkynyl; --C(O)R", wherein R" is selected from hydrogen, alkyl,substituted alkyl, alkoxy, alkylamino, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, aryloxy,arylamino, alkylaryl, substituted alkylaryl, arylalkyl, substitutedarylalkyl, heterocyclic, substituted heterocyclic or trifluoromethyl,provided, however, that the carbonyl functionality is not conjugatedwith an alkenyl or alkynyl functionality; --OR'", wherein R'" isselected from hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, alkylaryl, substitutedalkylaryl, arylalkyl, substituted arylalkyl, aroyl, substituted aroyl,heterocyclic, substituted heterocyclic, acyl, trifluoromethyl,alkylsulfonyl or arylsulfonyl, provided, however, that the --OR'"functionality is not conjugated with an alkenyl or alkynylfunctionality; --NR'"₂, wherein each R'" is independently as definedabove, or each R'" and the N to which they are attached can cooperate toform a 4-, 5-, 6- or 7-membered ring; provided, however, that the--NR'"₂ functionality is not conjugated with an alkenyl or alkynylfunctionality; --SR"", wherein R"" is selected from hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl,arylalkyl, substituted arylalkyl, heterocyclic, substituted heterocyclicor trifluoromethyl, provided, however, that the --SR"" functionality isnot conjugated with an alkenyl or alkynyl functionality; or --SiR'""₃,wherein R'"" is selected from alkyl or aryl; R⁷ is selected fromhydrogen, lower alkyl, aryl, substituted aryl, alkylaryl, or substitutedalkylaryl, or R⁷ is absent when there is a double bond between N⁷ and C⁸; and R⁹ and R^(9a) are each independently selected from hydrogen, loweralkyl, hydroxyalkyl, aryl, aryloxyalkyl, fluoro, trifluoromethyl, cyano,cyanomethyl, --OR', --NR'₂, or --SR', wherein each R' is as definedabove, provided, however, that neither the --NR'₂ nor the --SR'functionality is conjugated with an alkenyl or alkynylfunctionality;provided, however, that the following compounds areexcluded from the definition of Formula I: nicotine, nornicotine,anabasine, N-methyl anabasine, anabaseine, anatabine,N-methyl-2-oxoanabasine, myosmine, cotinine, the compounds whereinA=--CH₂ --, B=--CH₂ --, R² =H or Br, R⁴, R⁶, R⁹ and R^(9a) =H, R⁵ =H ormethyl, and R⁷ =methyl; compounds wherein A=--CH₂ --, B=--CH₂ --, R²,R⁴, R⁵ and R⁶ =H or alkyl, R⁷ is alkyl and R⁹ and R^(9a) =hydrogen;compounds wherein A=--CH₂ --, --C(O)-- or --CH(CH₂ F)--, B=--CHR^(10a)-- (wherein R^(10a) is H, lower alkyl, hydroxyalkyl, F, cyano,cyanomethyl or --OR', wherein R'=hydrogen or methyl), R², R⁴, R⁵ and R⁶=H, R⁷ is methyl and R⁹ and R^(9a) =hydrogen, methyl, fluorine,cyanomethyl, cyano or hydroxyalkyl; compounds wherein A=--CH₂ --, --CH₂CH₂ -- or --CH₂ CH═, B=--CH₂ -- or --CH═, R² and R⁶ =lower alkyl orarylalkyl, R⁴, R⁵, R⁹ and R^(9a) =H and R⁷ =hydrogen or methyl;compounds wherein A=--CH₂ --, B=--CH₂ --, R², R⁴, R⁵ and R⁶ =H, R⁷ andR⁹ are methyl and R^(9a) =hydrogen or methyl; compounds wherein A=--CH₂--, B=--CH₂ --, R², R⁴ and R⁶ =H or methyl, R⁵, R⁹ and R^(9a) arehydrogen, and R⁷ =methyl; compounds wherein A=--CH₂ -- or --C(O)--,B=--CH₂ --, R², R⁵, R⁶, R⁹ and R^(9a) are hydrogen, R⁴ =--NH₂ and R⁷=methyl; compounds wherein A=--CH₂ --, B=--CH₂ --, R², R⁴, R⁶, R⁷, R⁹and R^(9a) are hydrogen and R⁵ -bromine; compounds wherein A=--CH₂ --,B=--CH₂ --, R², R⁴, R⁶, R⁹ and R^(9a) are hydrogen, R⁵ =fluorine,chlorine, bromine, iodine, or --NH₂, and R⁷ =hydrogen or methyl;compounds wherein A=--CH₂ -- or --CH₂ CH₂ --, B=--CH₂ --, R², R⁴, R⁵ andR⁶ are alkyl or halogen, R⁷ =H or alkyl, and R⁹ and R^(9a) are alkyl;and compounds wherein A=--CH₂ CH₂ --, B=--CH₂ --, R², R⁴, R⁵ and R⁶ areH or lower alkyl, R⁷ =absent or H if the pyrrolidone ring contains nounsaturation, and R⁹ and R^(9a) are H or lower alkyl.
 2. A methodaccording to claim 1 wherein A of said compound is a 1, 2 or 3 atombridging species selected from alkylene, or --O--, --C(O)--, --N(R¹¹)--,and/or --S-containing alkylene moiety, wherein R¹¹ is hydrogen or alower alkyl moiety; provided, however, that the ring formed by N⁷, C⁸,C⁹, A and B does not contain any covalent heteroatom-heteroatom singlebonds, or any heteroatom-methylene-heteroatom bonding relationships. 3.A method according to claim 1 wherein A is --CH₂ --, --CH₂ CH₂ -- or--C(O)--.
 4. A method according to claim 1 wherein B is C¹⁰ HR^(10a) --,wherein R^(10a) is hydrogen or lower alkyl.
 5. A method according toclaim 4 wherein R^(10a) is hydrogen.
 6. A method according to claim 1wherein R² is hydrogen or amino.
 7. A method according to claim 1wherein R⁴ is hydrogen, aryl, alkoxy or aryloxy.
 8. A method accordingto claim 1 wherein R⁵ is alkynyl, aryl, substituted aryl, trialkylsilyl,arylalkyl, arylalkenyl or arylalkynyl.
 9. A method according to claim 1wherein R⁵ is an alkynyl moiety having the structure:

    --C.tbd.C--R.sup.5'

wherein R^(5') is hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, alkylaryl, substitutedalkylaryl, arylalkyl, substituted arylalkyl, heterocyclic, substitutedheterocyclic, trifluoromethyl, halogen, cyano, nitro; --S(O)R', --S(O)₂R' or --S(O)₂ NHR', wherein each R' is as defined above, provided,however, that when R², R⁴, R⁵ or R⁶ is --S(O)R', R' is not hydrogenalkenyl or alkynyl, and provided that when R², R⁴, R⁵ or R⁶ is --S(O)₂NHR', R' is not alkenyl or alkynyl; --C(O)R", wherein R" is hydrogen,alkyl, substituted alkyl, alkoxy, alkylamino, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, aryloxy,arylamino, alkylaryl, substituted alkylaryl, arylalkyl, substitutedarylalkyl, heterocyclic, substituted heterocyclic or trifluoromethyl,provided, however, that the carbonyl functionality is not conjugatedwith an alkenyl or alkynyl functionality; --OR'", wherein R'" ishydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl,substituted arylalkyl, aroyl, substituted aroyl, heterocyclic,substituted heterocyclic, acyl, trifluoromethyl, alkylsulfonyl orarylsulfonyl, provided, however, that the --OR'" functionality is notconjugated with an alkenyl or alkynyl functionality; --NR'"₂, whereineach R'" is independently as defined above, or each R'" and the N towhich they are attached can cooperate to form a 4-, 5-, 6- or 7-memberedring; provided, however, that the --NR'"₂ functionality is notconjugated with an alkenyl or alkynyl functionality; --SR"", wherein R""is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl,substituted alkylaryl, arylalkyl, substituted arylalkyl, heterocyclic,substituted heterocyclic or trifluoromethyl, provided, however, that the--SR"" functionality is not conjugated with an alkenyl or alkynylfunctionality; or --SiR'""₃, wherein R'"" is alkyl or aryl; alkylene,substituted alkylene, arylene, substituted arylene, so that theresulting compound is a polyfunctional species, bearing two or more ofthe substituted pyridyl structures contemplated by structure I.
 10. Amethod according to claim 9 wherein R^(5') is hydrogen, methyl, ethyl,propyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxymethyl,2-hydroxy-2-isopropyl, dimethylaminomethyl or phenyl.
 11. A methodaccording to claim 1 wherein R⁶ is hydrogen, chlorine, amino, methyl oralkoxy.
 12. A method according to claim 1 wherein R⁷ is absent, hydrogenor methyl.
 13. A method according to claim 1 wherein R⁹ and R^(9a) areeach independently hydrogen, lower alkyl, alkoxy or aryloxy.
 14. Amethod according to claim 1 wherein said compound is substantiallyoptically pure.
 15. A method according to claim 1 wherein said compoundis a racemic mixture or a diasteromeric mixture.
 16. A method accordingto claim 1 wherein A, B, R², R⁴, R⁵, R⁶, R⁷, R⁹ and R^(9a) are definedas follows:A=--CH₂ -- or --CH₂ CH₂ --, B=--CH₂ --, R² =hydrogen, R⁴=hydrogen, R⁵ =an alkynyl moiety having the structure:

    --C.tbd.C--R.sup.5'

wherein R^(5') is hydrogen, lower alkyl, hydroxyalkyl, alkoxyalkyl,dialkylaminoalkyl, aryl or 5- 1-(10- 5-(3-1-methyl-2-pyrrolidinyl!pyridine)-deca-1,9-diynyl, R⁶ =hydrogen, R⁷=hydrogen or methyl, R⁹ =hydrogen, and R^(9a) =hydrogen.
 17. A methodaccording to claim 16 wherein R^(5') is hydrogen, methyl, ethyl, propyl,hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxymethyl,1-hydroxyisopropyl, dimethylaminomethyl, or phenyl.
 18. A method fortreating cognitive dysfunction, said method comprising administering atherapeutically effective amount of a pharmaceutical compositioncomprising a compound of the structure ##STR12## and a pharmaceuticallyacceptable carrier therefor, optionally in the form of apharmaceutically acceptable non-toxic acid addition salt, wherein:A is a1, 2 or 3 atom bridging species which forms part of a saturated ormonounsaturated 5-, 6- or 7-membered ring including N⁷, C⁸, C⁹ and B; Bis selected from --O--, --S--, --NR¹⁰ --, wherein R¹⁰ is selected fromhydrogen, lower alkyl, aryl, substituted aryl, alkylaryl, substitutedalkylaryl, arylalkyl, substituted arylalkyl; --C¹⁰ HR^(10a) --, whereinR^(10a) is selected from hydrogen, lower alkyl, hydroxyalkyl, aryl,aryloxyalkyl, fluoro, trifluoromethyl, cyano, cyanomethyl, --OR',--NR'₂, or --SR', wherein each R' is independently hydrogen, loweralkyl, alkenyl, alkynyl or aryl, provided, however, that neither the--NR'₂ nor the --SR' functionality is conjugated with an alkenyl oralkynyl functionality; or B is ═C¹⁰ R^(10a) -- or ═N--, provided thereis no double bond in the ring between A and B, or between B and C⁹ whenthere is a double bond between N⁷ and C⁸, and provided that B is not aheteroatom when A is a 1 atom bridging species; R², R⁴, R⁵ and R⁶ areeach independently selected from hydrogen, alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl,substituted alkylaryl, arylalkyl, substituted arylalkyl, heterocyclic,substituted heterocyclic, trifluoromethyl, halogen, cyano,nitro;--S(O)R', --S(O)₂ R' or --S(O)₂ NHR', wherein each R' is asdefined above, provided, however, that when R², R⁴, R⁵ or R⁶ is--S(O)R', R' is not hydrogen, alkenyl or alkynyl, and provided that whenR², R⁴, R⁵ or R⁶ is S(O)₂ NHR', R' is not alkenyl or alkynyl; --C(O)R",wherein R" is selected from hydrogen, alkyl, substituted alkyl, alkoxy,alkylamino, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,aryl, substituted aryl, aryloxy, arylamino, alkylaryl, substitutedalkylaryl, arylalkyl, substituted arylalkyl, heterocyclic, substitutedheterocyclic or trifluoromethyl, provided, however, that the carbonylfunctionality is not conjugated with an alkenyl or alkynylfunctionality; --OR'", wherein R'" is selected from hydrogen, alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, alkylaryl, substituted alkylaryl, arylalkyl, substitutedarylalkyl, aroyl, substituted aroyl, heterocyclic, substitutedheterocyclic, acyl, trifluoromethyl, alkylsulfonyl or arylsulfonyl,provided, however, that the --OR'" functionality is not conjugated withan alkenyl or alkynyl functionality; --NR'"₂, wherein each R'" isindependently as defined above, or each R'" and the N to which they areattached can cooperate to form a 4-, 5-, 6- or 7-membered ring;provided, however, that the --NR'"₂ functionality is not conjugated withan alkenyl or alkynyl functionality; --SR"", wherein R"" is selectedfrom hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl,substituted alkylaryl, arylalkyl, substituted arylalkyl, heterocyclic,substituted heterocyclic or trifluoromethyl, provided, however, that the--SR"" functionality is not conjugated with an alkenyl or alkynylfunctionality; or --SiR'""₃, wherein R'"" is selected from alkyl oraryl; R⁷ is selected from hydrogen, lower alkyl, aryl, substituted aryl,alkylaryl, or substituted alkylaryl, or R⁷ is absent when there is adouble bond between N⁷ and C⁸ ; and R⁹ and R^(9a) are each independentlyselected from hydrogen, lower alkyl, hydroxyalkyl, aryl, aryloxyalkyl,fluoro, trifluoromethyl, cyano, cyanomethyl, --OR', --NR'₂, or --SR',wherein each R' is as defined above, provided, however, that neither the--NR'₂ nor the --SR' functionality is conjugated with an alkenyl oralkynyl functionality;provided, however, that the following compoundsare excluded from the definition of Formula I: nicotine, nornicotine,anabasine, N-methyl anabasine, anabaseine, anatabine,N-methyl-2-oxoanabasine, myosmine, cotinine, the compounds whereinA=--CH₂ --, B=--CH₂ --, R² =H or Br, R⁴, R⁶, R⁹ and R^(9a) =H, R⁵ =H ormethyl, and R⁷ =methyl; compounds wherein A=--CH₂ --, B=--CH₂ --, R²,R⁴, R⁵ and R⁶ =H or alkyl, R⁷ is alkyl and R⁹ and R^(9a) =hydrogen;compounds wherein A=--CH₂ --, --C(O)-- or --CH(CH₂ F)--, B=--CHR^(10a)-- (wherein R^(10a) is H, lower alkyl, hydroxyalkyl, F, cyano,cyanomethyl or --OR', wherein R'=hydrogen or methyl), R², R⁴, R⁵ and R⁶=H, R⁷ is methyl and R⁹ and R^(9a) =hydrogen, methyl, fluorine,cyanomethyl, cyano or hydroxyalkyl; compounds wherein A=--CH₂ --, --CH₂CH₂ -- or --CH₂ CH═, B=--CH₂ -- or --CH═, R² and R⁶ =lower alkyl orarylalkyl, R⁴, R⁵, R⁹ and R^(9a) =H and R⁷ =hydrogen or methyl;compounds wherein A=--CH₂ --, B=--CH₂ --, R², R⁴, R⁵ and R⁶ =H, R⁷ andR⁹ are methyl and R^(9a) =hydrogen or methyl; compounds wherein A=--CH₂--, B=--CH₂ --, R², R⁴ and R⁶ =H or methyl, R⁵, R⁹ and R^(9a) arehydrogen, and R⁷ =methyl; compounds wherein A=--CH₂ -- or --C(O)--,B=--CH₂ --, R², R⁵, R⁶, R⁹ and R^(9a) are hydrogen, R⁴ =--NH₂ and R⁷=methyl; compounds wherein A=--CH₂ --, B=--CH₂ --, R², R⁴, R⁶, R⁷, R⁹and R^(9a) are hydrogen and R⁵ =bromine; compounds wherein A=--CH₂ --,B=--CH₂ --, R², R⁴, R⁶, R⁹ and R^(9a) are hydrogen, R⁵ =fluorine,chlorine, bromine, iodine, or --NH₂, and R⁷ =hydrogen or methyl;compounds wherein A=--CH₂ -- or --CH₂ CH₂ --, B=--CH₂ --, R², R⁴, R⁵ andR⁶ are alkyl or halogen, R⁷ =H or alkyl, and R⁹ and R^(9a) are alkyl;and compounds wherein A=--CH₂ CH₂ --, B=--CH₂ --, R², R⁴, R⁵ and R⁶ areH or lower alkyl, R⁷ =absent or H if the pyrrolidone ring contains nounsaturation, and R⁹ and R^(9a) are H or lower alkyl.
 19. A methodaccording to claim 1 wherein A, B, R², R⁴, R⁵, R⁶, R⁷, R⁹ and R^(9a) aredefined as follows:A=--CH₂ --, B=--CH₂ --, R² =hydrogen, R⁴ =hydrogen,R⁵ =ethynyl, R⁶ =hydrogen, R⁷ =methyl, R⁹ =hydrogen, and R^(9a)=hydrogen.
 20. A method according to claim 1 wherein said cognitivedysfunction is an attention disorder.
 21. A method according to claim 1wherein said cognitive dysfunction is a disorder of the ability tofocus.
 22. A method according to claim 1 wherein said cognitivedysfunction is a disorder of the ability to concentrate.